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<record><TEI><teiHeader><fileDesc><titleStmt><title xml:lang="en">Forces and Disease: Electrostatic force differences caused by mutations in kinesin motor domains can distinguish between disease-causing and non-disease-causing mutations</title><author><name sortKey="Li, Lin" sort="Li, Lin" uniqKey="Li L" first="Lin" last="Li">Lin Li</name><affiliation><nlm:aff id="Aff1"><institution-wrap><institution-id institution-id-type="ISNI">0000 0001 0665 0280</institution-id><institution-id institution-id-type="GRID">grid.26090.3d</institution-id><institution>Department of Physics and Astronomy,</institution><institution>Clemson University,</institution></institution-wrap>Clemson, SC 29634 USA</nlm:aff></affiliation></author><author><name sortKey="Jia, Zhe" sort="Jia, Zhe" uniqKey="Jia Z" first="Zhe" last="Jia">Zhe Jia</name><affiliation><nlm:aff id="Aff1"><institution-wrap><institution-id institution-id-type="ISNI">0000 0001 0665 0280</institution-id><institution-id institution-id-type="GRID">grid.26090.3d</institution-id><institution>Department of Physics and Astronomy,</institution><institution>Clemson University,</institution></institution-wrap>Clemson, SC 29634 USA</nlm:aff></affiliation></author><author><name sortKey="Peng, Yunhui" sort="Peng, Yunhui" uniqKey="Peng Y" first="Yunhui" last="Peng">Yunhui Peng</name><affiliation><nlm:aff id="Aff1"><institution-wrap><institution-id institution-id-type="ISNI">0000 0001 0665 0280</institution-id><institution-id institution-id-type="GRID">grid.26090.3d</institution-id><institution>Department of Physics and Astronomy,</institution><institution>Clemson University,</institution></institution-wrap>Clemson, SC 29634 USA</nlm:aff></affiliation></author><author><name sortKey="Godar, Subash" sort="Godar, Subash" uniqKey="Godar S" first="Subash" last="Godar">Subash Godar</name><affiliation><nlm:aff id="Aff1"><institution-wrap><institution-id institution-id-type="ISNI">0000 0001 0665 0280</institution-id><institution-id institution-id-type="GRID">grid.26090.3d</institution-id><institution>Department of Physics and Astronomy,</institution><institution>Clemson University,</institution></institution-wrap>Clemson, SC 29634 USA</nlm:aff></affiliation></author><author><name sortKey="Getov, Ivan" sort="Getov, Ivan" uniqKey="Getov I" first="Ivan" last="Getov">Ivan Getov</name><affiliation><nlm:aff id="Aff2"><institution-wrap><institution-id institution-id-type="ISNI">0000 0001 0665 0280</institution-id><institution-id institution-id-type="GRID">grid.26090.3d</institution-id><institution>Department of Chemical Engineering,</institution><institution>Clemson University,</institution></institution-wrap>Clemson, SC 29634 USA</nlm:aff></affiliation></author><author><name sortKey="Teng, Shaolei" sort="Teng, Shaolei" uniqKey="Teng S" first="Shaolei" last="Teng">Shaolei Teng</name><affiliation><nlm:aff id="Aff3"><institution-wrap><institution-id institution-id-type="ISNI">0000 0001 0547 4545</institution-id><institution-id institution-id-type="GRID">grid.257127.4</institution-id><institution>Department of Biology,</institution><institution>Howard University,</institution></institution-wrap>Washington, DC 20059 USA</nlm:aff></affiliation></author><author><name sortKey="Alper, Joshua" sort="Alper, Joshua" uniqKey="Alper J" first="Joshua" last="Alper">Joshua Alper</name><affiliation><nlm:aff id="Aff1"><institution-wrap><institution-id institution-id-type="ISNI">0000 0001 0665 0280</institution-id><institution-id institution-id-type="GRID">grid.26090.3d</institution-id><institution>Department of Physics and Astronomy,</institution><institution>Clemson University,</institution></institution-wrap>Clemson, SC 29634 USA</nlm:aff></affiliation></author><author><name sortKey="Alexov, Emil" sort="Alexov, Emil" uniqKey="Alexov E" first="Emil" last="Alexov">Emil Alexov</name><affiliation><nlm:aff id="Aff1"><institution-wrap><institution-id institution-id-type="ISNI">0000 0001 0665 0280</institution-id><institution-id institution-id-type="GRID">grid.26090.3d</institution-id><institution>Department of Physics and Astronomy,</institution><institution>Clemson University,</institution></institution-wrap>Clemson, SC 29634 USA</nlm:aff></affiliation></author></titleStmt><publicationStmt><idno type="wicri:source">PMC</idno><idno type="pmid">28811629</idno><idno type="pmc">5557957</idno><idno type="url">http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5557957</idno><idno type="RBID">PMC:5557957</idno><idno type="doi">10.1038/s41598-017-08419-7</idno><date when="2017">2017</date><idno type="wicri:Area/Pmc/Corpus">000E45</idno><idno type="wicri:explorRef" wicri:stream="Pmc" wicri:step="Corpus" wicri:corpus="PMC">000E45</idno></publicationStmt><sourceDesc><biblStruct><analytic><title xml:lang="en" level="a" type="main">Forces and Disease: Electrostatic force differences caused by mutations in kinesin motor domains can distinguish between disease-causing and non-disease-causing mutations</title><author><name sortKey="Li, Lin" sort="Li, Lin" uniqKey="Li L" first="Lin" last="Li">Lin Li</name><affiliation><nlm:aff id="Aff1"><institution-wrap><institution-id institution-id-type="ISNI">0000 0001 0665 0280</institution-id><institution-id institution-id-type="GRID">grid.26090.3d</institution-id><institution>Department of Physics and Astronomy,</institution><institution>Clemson University,</institution></institution-wrap>Clemson, SC 29634 USA</nlm:aff></affiliation></author><author><name sortKey="Jia, Zhe" sort="Jia, Zhe" uniqKey="Jia Z" first="Zhe" last="Jia">Zhe Jia</name><affiliation><nlm:aff id="Aff1"><institution-wrap><institution-id institution-id-type="ISNI">0000 0001 0665 0280</institution-id><institution-id institution-id-type="GRID">grid.26090.3d</institution-id><institution>Department of Physics and Astronomy,</institution><institution>Clemson University,</institution></institution-wrap>Clemson, SC 29634 USA</nlm:aff></affiliation></author><author><name sortKey="Peng, Yunhui" sort="Peng, Yunhui" uniqKey="Peng Y" first="Yunhui" last="Peng">Yunhui Peng</name><affiliation><nlm:aff id="Aff1"><institution-wrap><institution-id institution-id-type="ISNI">0000 0001 0665 0280</institution-id><institution-id institution-id-type="GRID">grid.26090.3d</institution-id><institution>Department of Physics and Astronomy,</institution><institution>Clemson University,</institution></institution-wrap>Clemson, SC 29634 USA</nlm:aff></affiliation></author><author><name sortKey="Godar, Subash" sort="Godar, Subash" uniqKey="Godar S" first="Subash" last="Godar">Subash Godar</name><affiliation><nlm:aff id="Aff1"><institution-wrap><institution-id institution-id-type="ISNI">0000 0001 0665 0280</institution-id><institution-id institution-id-type="GRID">grid.26090.3d</institution-id><institution>Department of Physics and Astronomy,</institution><institution>Clemson University,</institution></institution-wrap>Clemson, SC 29634 USA</nlm:aff></affiliation></author><author><name sortKey="Getov, Ivan" sort="Getov, Ivan" uniqKey="Getov I" first="Ivan" last="Getov">Ivan Getov</name><affiliation><nlm:aff id="Aff2"><institution-wrap><institution-id institution-id-type="ISNI">0000 0001 0665 0280</institution-id><institution-id institution-id-type="GRID">grid.26090.3d</institution-id><institution>Department of Chemical Engineering,</institution><institution>Clemson University,</institution></institution-wrap>Clemson, SC 29634 USA</nlm:aff></affiliation></author><author><name sortKey="Teng, Shaolei" sort="Teng, Shaolei" uniqKey="Teng S" first="Shaolei" last="Teng">Shaolei Teng</name><affiliation><nlm:aff id="Aff3"><institution-wrap><institution-id institution-id-type="ISNI">0000 0001 0547 4545</institution-id><institution-id institution-id-type="GRID">grid.257127.4</institution-id><institution>Department of Biology,</institution><institution>Howard University,</institution></institution-wrap>Washington, DC 20059 USA</nlm:aff></affiliation></author><author><name sortKey="Alper, Joshua" sort="Alper, Joshua" uniqKey="Alper J" first="Joshua" last="Alper">Joshua Alper</name><affiliation><nlm:aff id="Aff1"><institution-wrap><institution-id institution-id-type="ISNI">0000 0001 0665 0280</institution-id><institution-id institution-id-type="GRID">grid.26090.3d</institution-id><institution>Department of Physics and Astronomy,</institution><institution>Clemson University,</institution></institution-wrap>Clemson, SC 29634 USA</nlm:aff></affiliation></author><author><name sortKey="Alexov, Emil" sort="Alexov, Emil" uniqKey="Alexov E" first="Emil" last="Alexov">Emil Alexov</name><affiliation><nlm:aff id="Aff1"><institution-wrap><institution-id institution-id-type="ISNI">0000 0001 0665 0280</institution-id><institution-id institution-id-type="GRID">grid.26090.3d</institution-id><institution>Department of Physics and Astronomy,</institution><institution>Clemson University,</institution></institution-wrap>Clemson, SC 29634 USA</nlm:aff></affiliation></author></analytic><series><title level="j">Scientific Reports</title><idno type="eISSN">2045-2322</idno><imprint><date when="2017">2017</date></imprint></series></biblStruct></sourceDesc></fileDesc><profileDesc><textClass></textClass></profileDesc></teiHeader><front><div type="abstract" xml:lang="en"><p id="Par1">The ability to predict if a given mutation is disease-causing or not has enormous potential to impact human health. Typically, these predictions are made by assessing the effects of mutation on macromolecular stability and amino acid conservation. Here we report a novel feature: the electrostatic component of the force acting between a kinesin motor domain and tubulin. We demonstrate that changes in the electrostatic component of the binding force are able to discriminate between disease-causing and non-disease-causing mutations found in human kinesin motor domains using the receiver operating characteristic (ROC). Because diseases may originate from multiple effects not related to kinesin-microtubule binding, the prediction rate of 0.843 area under the ROC plot due to the change in magnitude of the electrostatic force alone is remarkable. These results reflect the dependence of kinesin’s function on motility along the microtubule, which suggests a precise balance of microtubule binding forces is required.</p></div></front><back><div1 type="bibliography"><listBibl><biblStruct><analytic><author><name sortKey="Srinivasan, S" uniqKey="Srinivasan S">S Srinivasan</name></author><author><name sortKey="Clements, Ja" uniqKey="Clements J">JA Clements</name></author><author><name sortKey="Batra, J" uniqKey="Batra J">J Batra</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Brookes, Aj" uniqKey="Brookes A">AJ Brookes</name></author><author><name sortKey="Robinson, Pn" uniqKey="Robinson P">PN Robinson</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Leu, C" uniqKey="Leu C">C Leu</name></author><author><name sortKey="Coppola, A" uniqKey="Coppola A">A Coppola</name></author><author><name sortKey="Sisodiya, Sm" uniqKey="Sisodiya S">SM 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<front><journal-meta><journal-id journal-id-type="nlm-ta">Sci Rep</journal-id><journal-id journal-id-type="iso-abbrev">Sci Rep</journal-id><journal-title-group><journal-title>Scientific Reports</journal-title></journal-title-group><issn pub-type="epub">2045-2322</issn><publisher><publisher-name>Nature Publishing Group UK</publisher-name><publisher-loc>London</publisher-loc></publisher></journal-meta><article-meta><article-id pub-id-type="pmid">28811629</article-id><article-id pub-id-type="pmc">5557957</article-id><article-id pub-id-type="publisher-id">8419</article-id><article-id pub-id-type="doi">10.1038/s41598-017-08419-7</article-id><article-categories><subj-group subj-group-type="heading"><subject>Article</subject></subj-group></article-categories><title-group><article-title>Forces and Disease: Electrostatic force differences caused by mutations in kinesin motor domains can distinguish between disease-causing and non-disease-causing mutations</article-title></title-group><contrib-group><contrib contrib-type="author" equal-contrib="yes"><name><surname>Li</surname><given-names>Lin</given-names></name><xref ref-type="aff" rid="Aff1">1</xref></contrib><contrib contrib-type="author" equal-contrib="yes"><name><surname>Jia</surname><given-names>Zhe</given-names></name><xref ref-type="aff" rid="Aff1">1</xref></contrib><contrib contrib-type="author"><name><surname>Peng</surname><given-names>Yunhui</given-names></name><xref ref-type="aff" rid="Aff1">1</xref></contrib><contrib contrib-type="author"><name><surname>Godar</surname><given-names>Subash</given-names></name><xref ref-type="aff" rid="Aff1">1</xref></contrib><contrib contrib-type="author"><name><surname>Getov</surname><given-names>Ivan</given-names></name><xref ref-type="aff" rid="Aff2">2</xref></contrib><contrib contrib-type="author"><name><surname>Teng</surname><given-names>Shaolei</given-names></name><xref ref-type="aff" rid="Aff3">3</xref></contrib><contrib contrib-type="author" corresp="yes"><contrib-id contrib-id-type="orcid">http://orcid.org/0000-0003-1235-8694</contrib-id><name><surname>Alper</surname><given-names>Joshua</given-names></name><address><email>alper@clemson.edu</email></address><xref ref-type="aff" rid="Aff1">1</xref></contrib><contrib contrib-type="author" corresp="yes"><contrib-id contrib-id-type="orcid">http://orcid.org/0000-0001-5346-0156</contrib-id><name><surname>Alexov</surname><given-names>Emil</given-names></name><address><email>ealexov@clemson.edu</email></address><xref ref-type="aff" rid="Aff1">1</xref></contrib><aff id="Aff1"><label>1</label><institution-wrap><institution-id institution-id-type="ISNI">0000 0001 0665 0280</institution-id><institution-id institution-id-type="GRID">grid.26090.3d</institution-id><institution>Department of Physics and Astronomy,</institution><institution>Clemson University,</institution></institution-wrap>Clemson, SC 29634 USA</aff><aff id="Aff2"><label>2</label><institution-wrap><institution-id institution-id-type="ISNI">0000 0001 0665 0280</institution-id><institution-id institution-id-type="GRID">grid.26090.3d</institution-id><institution>Department of Chemical Engineering,</institution><institution>Clemson University,</institution></institution-wrap>Clemson, SC 29634 USA</aff><aff id="Aff3"><label>3</label><institution-wrap><institution-id institution-id-type="ISNI">0000 0001 0547 4545</institution-id><institution-id institution-id-type="GRID">grid.257127.4</institution-id><institution>Department of Biology,</institution><institution>Howard University,</institution></institution-wrap>Washington, DC 20059 USA</aff></contrib-group><pub-date pub-type="epub"><day>15</day><month>8</month><year>2017</year></pub-date><pub-date pub-type="pmc-release"><day>15</day><month>8</month><year>2017</year></pub-date><pub-date pub-type="collection"><year>2017</year></pub-date><volume>7</volume><elocation-id>8237</elocation-id><history><date date-type="received"><day>28</day><month>2</month><year>2017</year></date><date date-type="accepted"><day>10</day><month>7</month><year>2017</year></date></history><permissions><copyright-statement>© The Author(s) 2017</copyright-statement><license license-type="OpenAccess"><license-p><bold>Open Access</bold> This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit <ext-link ext-link-type="uri" xlink:href="http://creativecommons.org/licenses/by/4.0/">http://creativecommons.org/licenses/by/4.0/</ext-link>.</license-p></license></permissions><abstract id="Abs1"><p id="Par1">The ability to predict if a given mutation is disease-causing or not has enormous potential to impact human health. Typically, these predictions are made by assessing the effects of mutation on macromolecular stability and amino acid conservation. Here we report a novel feature: the electrostatic component of the force acting between a kinesin motor domain and tubulin. We demonstrate that changes in the electrostatic component of the binding force are able to discriminate between disease-causing and non-disease-causing mutations found in human kinesin motor domains using the receiver operating characteristic (ROC). Because diseases may originate from multiple effects not related to kinesin-microtubule binding, the prediction rate of 0.843 area under the ROC plot due to the change in magnitude of the electrostatic force alone is remarkable. These results reflect the dependence of kinesin’s function on motility along the microtubule, which suggests a precise balance of microtubule binding forces is required.</p></abstract><custom-meta-group><custom-meta><meta-name>issue-copyright-statement</meta-name><meta-value>© The Author(s) 2017</meta-value></custom-meta></custom-meta-group></article-meta></front><body><sec id="Sec1" sec-type="introduction"><title>Introduction</title><p id="Par2">The ability to predict if genetic mutations cause disease or not has enormous potential to impact human health<sup><xref ref-type="bibr" rid="CR1">1</xref>, <xref ref-type="bibr" rid="CR2">2</xref></sup>. Efforts to make these predictions to date have largely been done by assessing the effect of a genetic mutation on the coded protein’s stability and amino acid conservation<sup><xref ref-type="bibr" rid="CR3">3</xref>, <xref ref-type="bibr" rid="CR4">4</xref></sup>. While these predictions have had some success based on genome-wide work<sup><xref ref-type="bibr" rid="CR5">5</xref></sup>, when considering the disease-causing effects of mutations in particular protein families, other, more function specific, features may be more successful<sup><xref ref-type="bibr" rid="CR6">6</xref>, <xref ref-type="bibr" rid="CR7">7</xref></sup>.</p><p id="Par3">The kinesin superfamily of microtubule motor proteins is responsible for a diverse set of cell biological functions including intracellular transport, ciliary assembly, mitosis, meiosis, cytoskeletal morphology, and microtubule dynamics regulation<sup><xref ref-type="bibr" rid="CR8">8</xref>, <xref ref-type="bibr" rid="CR9">9</xref></sup>. These functions depend on kinesin’s force generating and motile properties<sup><xref ref-type="bibr" rid="CR10">10</xref>, <xref ref-type="bibr" rid="CR11">11</xref></sup>. Kinesins, for example, are particularly critical to the development of neurons due to their ability to transport intracellular cargos, including synaptic vesicles, mitochondria, and newly synthesized protein complexes from the endoplasmic reticulum near the nucleus in the cell body to the growing tips of axons and dendrites<sup><xref ref-type="bibr" rid="CR12">12</xref></sup>. Kinesins enable elongated neurons, sometimes more than a meter long, to overcome physical limitations associated with long distance diffusion<sup><xref ref-type="bibr" rid="CR13">13</xref></sup>.</p><p id="Par4">To accomplish the diversity of functions that kinesins perform, there are 14 recognized and numbered families of kinesins<sup><xref ref-type="bibr" rid="CR8">8</xref>, <xref ref-type="bibr" rid="CR14">14</xref></sup>, as well as numerous ungrouped, or orphan, kinesins<sup><xref ref-type="bibr" rid="CR8">8</xref></sup>. Most members of the kinesin superfamily are microtubule plus end-directed motors<sup><xref ref-type="bibr" rid="CR12">12</xref></sup>. Some notable exceptions include kinesin-13s, which are primarily involved in regulation of microtubule dynamics<sup><xref ref-type="bibr" rid="CR15">15</xref></sup> and move by diffusion<sup><xref ref-type="bibr" rid="CR16">16</xref></sup>, and kinesin-14s, which are minus end-directed motors<sup><xref ref-type="bibr" rid="CR17">17</xref>, <xref ref-type="bibr" rid="CR18">18</xref></sup>. Kinesin motor motility and pN-scale forces arise from structural changes in the neck linker subdomains<sup><xref ref-type="bibr" rid="CR19">19</xref>, <xref ref-type="bibr" rid="CR20">20</xref></sup> of kinesins upon hydrolysis of ATP<sup><xref ref-type="bibr" rid="CR21">21</xref></sup>. However, these forces are not the only forces within kinesins that are critical to their function.</p><p id="Par5">The forces of binding between a kinesin and the microtubule are additionally important to the motor’s processivity, which is a motility property determined by how far it moves along a microtubule before completely dissociating<sup><xref ref-type="bibr" rid="CR13">13</xref></sup>. A single bound kinesin motor domain is in a state of force equilibrium in the absence of external loading, meaning that the sum of all forces between the microtubule and the kinesin must be zero. These forces are electrostatic and non-electrostatic forces, including hydrogen bonds and salt bridges, van der Waals forces, as well as others. However, because the charge of amino acids at the microtubule binding interface greatly affects the motility and microtubule-stimulated ATPase rate of kinesin<sup><xref ref-type="bibr" rid="CR22">22</xref></sup>, the dominant force associated with binding is likely the electrostatic force. Electrostatic forces guide kinesin-1 to its binding site<sup><xref ref-type="bibr" rid="CR23">23</xref></sup> and allow it to follow a single protofilament<sup><xref ref-type="bibr" rid="CR24">24</xref>, <xref ref-type="bibr" rid="CR25">25</xref></sup>. Electrostatic forces also likely underlie the diffusive motility of kinesin-8<sup><xref ref-type="bibr" rid="CR26">26</xref>, <xref ref-type="bibr" rid="CR27">27</xref></sup> and kinesin-13<sup><xref ref-type="bibr" rid="CR16">16</xref></sup>.</p><p id="Par6">Kinesins are critical to cell biology, so they are also important to many aspects of life, particularly to cell division and the nervous system. Genetic defects in kinesin motor domains that cause errors in cell division are likely embryonic lethal. Somatic defects are found in and are distributed throughout many kinesins, including the motor domains<sup><xref ref-type="bibr" rid="CR28">28</xref></sup>. These defects are prevalent in endometrial cancer, lung squamous cell carcinoma, and melanoma<sup><xref ref-type="bibr" rid="CR28">28</xref></sup>. However, somatic defects are generally unique to single samples making it difficult to discern their significance to the cancer<sup><xref ref-type="bibr" rid="CR28">28</xref></sup>. Multiple congenital disorders are caused by non-synonymous single nucleotide polymorphisms (nsSNPs) in kinesin motor domains, including nsSNPs in the kinesin-1 family member KIF5A that cause parkinsonism<sup><xref ref-type="bibr" rid="CR29">29</xref></sup>, peripheral neuropathy<sup><xref ref-type="bibr" rid="CR29">29</xref>–<xref ref-type="bibr" rid="CR32">32</xref></sup>, Charcot–Marie–Tooth disease type 2<sup><xref ref-type="bibr" rid="CR33">33</xref></sup>, retinitis pigmentosa<sup><xref ref-type="bibr" rid="CR29">29</xref></sup>, and spastic paraplegia<sup><xref ref-type="bibr" rid="CR33">33</xref>–<xref ref-type="bibr" rid="CR35">35</xref></sup>; nsSNPs in the kinesin-1 family member KIF5C and the kinesin-5 family member KIF11 that cause microcephaly<sup><xref ref-type="bibr" rid="CR36">36</xref>, <xref ref-type="bibr" rid="CR37">37</xref></sup>; nsSNPs in the kinesin-10 family member KIF22 that cause lepto-spondyloepimetaphyseal dysplasia<sup><xref ref-type="bibr" rid="CR38">38</xref></sup>; nsSNPs in the kinesin-3 family member KIF1A that cause spastic paraparesis and sensory and autonomic neuropathy type-2<sup><xref ref-type="bibr" rid="CR39">39</xref></sup>; and nsSNPs in the kinesin-5 family member KIF11 that cause primary lymphedema and chorioretinal dysplasia<sup><xref ref-type="bibr" rid="CR37">37</xref></sup>.</p><p id="Par7">Because nsSNPs in kinesins tend to cause neurological genetic disorders and electrostatic forces between the kinesin motor domain and the microtubule are critical to multiple physiological properties of kinesins that could be particularly important in neurons, we hypothesized that the nsSNPs found in kinesin motor domains that greatly affect the electrostatic forces acting between kinesin and microtubules would strongly correlate to the nsSNPs causing human disease. To probe this hypothesis, we investigated the effect of known kinesin motor domain nsSNPs on the electrostatic force between kinesin and tubulin dimers using computational techniques. This study is based on 50 nsSNPs causing missense mutations in the motor domains of 10 different genes coding for proteins from 8 different kinesin families identified from dbNSFP<sup><xref ref-type="bibr" rid="CR40">40</xref></sup> and annotated as disease-causing using the Human Gene Mutation Database<sup><xref ref-type="bibr" rid="CR41">41</xref></sup> and ClinVar<sup><xref ref-type="bibr" rid="CR42">42</xref></sup> complemented with 11 nsSNPs that do not cause disease taken from 1000 genomes project<sup><xref ref-type="bibr" rid="CR43">43</xref></sup>. The goal is to determine whether the changes in the electrostatic forces caused by mutations can be used to discriminate disease-causing mutations from those that do not cause human disease.</p></sec><sec id="Sec2" sec-type="materials|methods"><title>Materials and Methods</title><sec id="Sec3"><title>Selection of kinesin nsSNPs</title><p id="Par8">The kinesin nsSNPs were downloaded from dbNSFP<sup><xref ref-type="bibr" rid="CR40">40</xref></sup> and missense mutations located in the coding regions of the kinesin motors domains with structures available in the PDB<sup><xref ref-type="bibr" rid="CR44">44</xref></sup> were selected. The Human Gene Mutation Database (HGMD)<sup><xref ref-type="bibr" rid="CR41">41</xref></sup> and ClinVar<sup><xref ref-type="bibr" rid="CR42">42</xref></sup> were used to identify disease-causing mutations. This resulted in the selection of 50 mutations in various kinesins.</p><p id="Par9">A total of 11 nsSNPs with the allele frequency greater than 1% in the 1000 Genomes Project<sup><xref ref-type="bibr" rid="CR45">45</xref></sup> were identified and used as common, non-disease causing polymorphisms in the healthy individuals.</p><p id="Par10">Note that significantly more disease-causing mutations were identified than non-disease-causing mutations, but the inclusion of mutations with allele frequency smaller than 1% may result in mutations with unknown physiological importance. The list of all the mutations for this study is provided in Supplementary Materials Table <xref rid="MOESM1" ref-type="media">S1</xref>.</p></sec><sec id="Sec4"><title>Preparation of kinesin-tubulin structures</title><p id="Par11">The 61 selected mutants come from 10 kinesin proteins representing 8 kinesin families (Table <xref rid="Tab1" ref-type="table">1</xref>). High resolution structures, those with better than 5 Å resolution and having no mutation, were downloaded from the Protein Data Bank (PDB)<sup><xref ref-type="bibr" rid="CR46">46</xref></sup> for 5 of the 10 kinesin proteins. If multiple structures were available for the same kinesin in PDB, the structure with the highest resolution was selected for this work.<table-wrap id="Tab1"><label>Table 1</label><caption><p>Details of the 10 wild type kinesin structures used.</p></caption><table frame="hsides" rules="groups"><thead><tr><th>Kinesin family</th><th>Human protein name</th><th>PDB:</th><th>Template</th><th>Nucleotide state of motor</th><th>Sequence Similarity (%)</th><th>X-ray resolution (Å)</th><th>Ref.</th></tr></thead><tbody><tr><td>Kinesin-1</td><td>KIF5A</td><td>Swiss model</td><td>3WRD.A – mouse kinesin 1 (KIF5C)</td><td>apo</td><td>91.2</td><td>2.9</td><td><xref ref-type="bibr" rid="CR71">71</xref></td></tr><tr><td>Kinesin-1</td><td>KIF5C</td><td>Swiss model</td><td>5HNY.C – rat kinesin 1/Drosophila kinesin 14 chimera (KIF5C/NCD)</td><td>AMPPNP</td><td>97.8</td><td>6.3</td><td><xref ref-type="bibr" rid="CR72">72</xref></td></tr><tr><td>Kinesin-3</td><td>KIF1A</td><td>Swiss model</td><td>2HXH.C – mouse kinesin 3 (KIF1A)</td><td>ADP</td><td>95.9</td><td>11</td><td><xref ref-type="bibr" rid="CR73">73</xref></td></tr><tr><td>Kinesin-4</td><td>KIF21A</td><td>Swiss model</td><td>3ZFD.A – mouse kinesin 4 (KIF4)</td><td>AMPPNP</td><td>57.1</td><td>1.7</td><td><xref ref-type="bibr" rid="CR74">74</xref></td></tr><tr><td>Kinesin-4</td><td>KIF27</td><td>Swiss model</td><td>3ZFD.A - mouse kinesin 4 (KIF4)</td><td>AMPPNP</td><td>52.5</td><td>1.7</td><td><xref ref-type="bibr" rid="CR74">74</xref></td></tr><tr><td>Kinesin-5</td><td>KIF11</td><td>1II6.A</td><td></td><td>ADP</td><td></td><td>2.1</td><td><xref ref-type="bibr" rid="CR75">75</xref></td></tr><tr><td>Kinesin-8</td><td>KIF18A</td><td>3LRE.A</td><td></td><td>ADP</td><td></td><td>2.2</td><td><xref ref-type="bibr" rid="CR68">68</xref></td></tr><tr><td>Kinesin-9</td><td>KIF9</td><td>3NWN.A</td><td></td><td>ADP</td><td></td><td>2.0</td><td><xref ref-type="bibr" rid="CR44">44</xref></td></tr><tr><td>Kinesin-10</td><td>KIF22</td><td>3BFN.A</td><td></td><td>ADP</td><td></td><td>2.3</td><td><xref ref-type="bibr" rid="CR44">44</xref></td></tr><tr><td>Kinesin-13</td><td>KIF2C</td><td>2HEH.A</td><td></td><td>ADP</td><td></td><td>2.2</td><td><xref ref-type="bibr" rid="CR44">44</xref></td></tr></tbody></table></table-wrap></p><p id="Par12">High resolution structures were not available in the PDB for the other 5 kinesin proteins. Note that for some proteins, including KIF1A and KIF5A, structures were available, however, either the resolution was too low or the structure had mutations introduced into it. In the cases without structure, SWISS-MODEL<sup><xref ref-type="bibr" rid="CR47">47</xref></sup> was used to build protein homology models from templates with high sequence similarities. The top model from SWISS-MODEL was selected to model the corresponding kinesin motor structures.</p><p id="Par13">Some of the structures had missing heavy atoms. Profix<sup><xref ref-type="bibr" rid="CR48">48</xref></sup> was used to fix these structures.</p><p id="Par14">NAMD<sup><xref ref-type="bibr" rid="CR49">49</xref></sup> was used to perform a 10,000-step energy minimization for each structure. In NAMD minimizations, the CHARMM<sup><xref ref-type="bibr" rid="CR50">50</xref></sup> force field and the Generalized Born (GB) implicit solvent model were used.</p><p id="Par15">There were no structures of the human kinesin-human tubulin complex available in PDB. However, there were many other kinesin-tubulin complex structures available, and kinesins share the same microtubule binding site<sup><xref ref-type="bibr" rid="CR22">22</xref>, <xref ref-type="bibr" rid="CR51">51</xref></sup>. Therefore, kinesin-tubulin complex structures were made using Chimera<sup><xref ref-type="bibr" rid="CR52">52</xref></sup> to align each kinesin (Table <xref rid="Tab1" ref-type="table">1</xref>) to the human α1A/β3 tubulin dimer structure (PDB ID 5JCO)<sup><xref ref-type="bibr" rid="CR53">53</xref></sup>, using a model of human kinesin-5 and a mammalian tubulin dimer docked into a 9.5- Å cryo-EM map (PDB ID 4AQW)<sup><xref ref-type="bibr" rid="CR54">54</xref></sup> as a template. The C-termini (E-hooks) were not modeled since their structures are not available in the corresponding PDB files.</p><p id="Par16">Building complex structure via structural alignment of the backbone atoms resulted in atomic clashes at the binding interface. To remove these structural clashes introduced during the modeling process, the kinesin-tubulin complex structures underwent 2000 steps of energy minimization using the CHARMM36<sup><xref ref-type="bibr" rid="CR55">55</xref></sup> force field in CHARMM<sup><xref ref-type="bibr" rid="CR56">56</xref></sup> software in which only amino acid side chains were free to move because a 10 kcal·mol<sup>−1</sup>·Å<sup>−1</sup> harmonic constraint was placed on all backbone atoms.</p><p id="Par17">The nsSNP structures were generated based on the wild type structure for each kinesin using PDB2PQR<sup><xref ref-type="bibr" rid="CR57">57</xref></sup>. The protonation states of titratable group were assumed to be standard, roughly corresponding to pH = 7.0. Since the kinesins considered in this work are cytoplasmic kinesins, the physiological pH is 7.0. Only the mutated residue was energy optimized; all other atoms were kept in the same position as in the wild type structure to isolate the direct effects of electrostatic forces.</p></sec><sec id="Sec5"><title>Force calculations</title><p id="Par18">Electrostatic forces were calculated for each kinesin-tubulin complex using DelPhiForce<sup><xref ref-type="bibr" rid="CR58">58</xref></sup>. The force reported is the net electrostatic force exerted on a kinesin by its tubulin dimer binding partner. The electrostatic force on each individual atom and residue, which is used to analyze the detailed force distribution on each kinesin, was also calculated with DelPhiForce.</p><p id="Par19">The forces on each kinesin were calculated in two states: the bound state and the unbound state. The bound state was considered to be the equilibrium complex position, which was determined as described in “Preparation of kinesin-tubulin structures”. The unbound state was obtained by displacing the kinesin 5 Å from the tubulin in the direction along the line between the mass center of the kinesin and tubulin dimer. The dielectric constant for water and protein were set as 80 and 2, respectively; the resolution of the grid was set at 2 grids/Å; the perfil was set at 70; the ionic strength of the solvent was set at 0 (zero salt concentration was used to be consistent with our previous studies and to avoid the ambiguity associated with explicit ion binding). However, to check the sensitivity of results, parallel calculations were done at physiological salt concentration corresponding to ionic strength I = 0.15 M. The dipolar boundary condition was used in all cases. Information on these parameters is available in the DelPhi<sup><xref ref-type="bibr" rid="CR59">59</xref>, <xref ref-type="bibr" rid="CR60">60</xref></sup> manual (<ext-link ext-link-type="uri" xlink:href="http://compbio.clemson.edu/downloadDir/delphi/delphi_manual.pdf">http://compbio.clemson.edu/downloadDir/delphi/delphi_manual.pdf</ext-link>).</p><p id="Par20">The electrostatic force difference, <inline-formula id="IEq1"><alternatives><tex-math id="M1">\documentclass[12pt]{minimal}
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\begin{document}$${\rm{\Delta }}\bar{F}$$\end{document}</tex-math><mml:math id="M2"><mml:mi mathvariant="normal">Δ</mml:mi><mml:mover accent="true"><mml:mi>F</mml:mi><mml:mo>¯</mml:mo></mml:mover></mml:math><inline-graphic xlink:href="41598_2017_8419_Article_IEq1.gif"></inline-graphic></alternatives></inline-formula>, was defined as the difference between the electrostatic forces exerted on wild type and the corresponding mutant kinesins.<disp-formula id="Equ1"><label>1</label><alternatives><tex-math id="M3">\documentclass[12pt]{minimal}
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\begin{document}$${\rm{\Delta }}\bar{F}={\bar{F}}_{{\rm{mut}}}-{\bar{F}}_{{\rm{wt}}}$$\end{document}</tex-math><mml:math id="M4" display="block"><mml:mi mathvariant="normal">Δ</mml:mi><mml:mover accent="true"><mml:mi>F</mml:mi><mml:mo>¯</mml:mo></mml:mover><mml:mo>=</mml:mo><mml:msub><mml:mrow><mml:mover accent="true"><mml:mi>F</mml:mi><mml:mo>¯</mml:mo></mml:mover></mml:mrow><mml:mrow><mml:mi mathvariant="normal">mut</mml:mi></mml:mrow></mml:msub><mml:mo>−</mml:mo><mml:msub><mml:mrow><mml:mover accent="true"><mml:mi>F</mml:mi><mml:mo>¯</mml:mo></mml:mover></mml:mrow><mml:mrow><mml:mi mathvariant="normal">wt</mml:mi></mml:mrow></mml:msub></mml:math><graphic xlink:href="41598_2017_8419_Article_Equ1.gif" position="anchor"></graphic></alternatives></disp-formula>where <inline-formula id="IEq2"><alternatives><tex-math id="M5">\documentclass[12pt]{minimal}
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\begin{document}$${\rm{\Delta }}\bar{F}$$\end{document}</tex-math><mml:math id="M6"><mml:mi mathvariant="normal">Δ</mml:mi><mml:mover accent="true"><mml:mi>F</mml:mi><mml:mo>¯</mml:mo></mml:mover></mml:math><inline-graphic xlink:href="41598_2017_8419_Article_IEq2.gif"></inline-graphic></alternatives></inline-formula> and are vector quantities with components Δ<italic>F</italic><sub>lat</sub> (lateral direction), Δ<italic>F</italic><sub>long</sub> (longitude direction), and Δ<italic>F</italic><sub>bind</sub> (binding direction).</p><p id="Par21">The relative force difference Δ<italic>F</italic><sub>rel</sub> is defined as:<disp-formula id="Equ2"><label>2</label><alternatives><tex-math id="M7">\documentclass[12pt]{minimal}
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\begin{document}$${\rm{\Delta }}{F}_{{\rm{rel}}}=|{\bar{F}}_{{\rm{mut}}}-{\bar{F}}_{{\rm{wt}}}|/|{\bar{F}}_{{\rm{wt}}}|$$\end{document}</tex-math><mml:math id="M8" display="block"><mml:mi mathvariant="normal">Δ</mml:mi><mml:msub><mml:mrow><mml:mi>F</mml:mi></mml:mrow><mml:mrow><mml:mi mathvariant="normal">rel</mml:mi></mml:mrow></mml:msub><mml:mo>=</mml:mo><mml:mrow><mml:mo stretchy="true">|</mml:mo><mml:mrow><mml:msub><mml:mrow><mml:mover accent="true"><mml:mi>F</mml:mi><mml:mo>¯</mml:mo></mml:mover></mml:mrow><mml:mrow><mml:mi mathvariant="normal">mut</mml:mi></mml:mrow></mml:msub><mml:mo>−</mml:mo><mml:msub><mml:mrow><mml:mover accent="true"><mml:mi>F</mml:mi><mml:mo>¯</mml:mo></mml:mover></mml:mrow><mml:mrow><mml:mi mathvariant="normal">wt</mml:mi></mml:mrow></mml:msub></mml:mrow><mml:mo stretchy="true">|</mml:mo></mml:mrow><mml:mo>/</mml:mo><mml:mrow><mml:mo stretchy="true">|</mml:mo><mml:mrow><mml:msub><mml:mrow><mml:mover accent="true"><mml:mi>F</mml:mi><mml:mo>¯</mml:mo></mml:mover></mml:mrow><mml:mrow><mml:mi mathvariant="normal">wt</mml:mi></mml:mrow></mml:msub></mml:mrow><mml:mo stretchy="true">|</mml:mo></mml:mrow></mml:math><graphic xlink:href="41598_2017_8419_Article_Equ2.gif" position="anchor"></graphic></alternatives></disp-formula></p><p id="Par22">The relative force difference in the binding direction Δ<italic>F</italic><sub><italic>bind,rel</italic></sub> is defined as<disp-formula id="Equ3"><label>3</label><alternatives><tex-math id="M9">\documentclass[12pt]{minimal}
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\begin{document}$${\rm{\Delta }}{F}_{{\rm{b}}{\rm{i}}{\rm{n}}{\rm{d}},{\rm{r}}{\rm{e}}{\rm{l}}}=|{\bar{F}}_{{\rm{b}}{\rm{i}}{\rm{n}}{\rm{d}},{\rm{m}}{\rm{u}}{\rm{t}}}-{\bar{F}}_{{\rm{b}}{\rm{i}}{\rm{n}}{\rm{d}},{\rm{w}}{\rm{t}}}|/|{\bar{F}}_{{\rm{b}}{\rm{i}}{\rm{n}}{\rm{d}},{\rm{w}}{\rm{t}}}|$$\end{document}</tex-math><mml:math id="M10" display="block"><mml:mrow><mml:mrow><mml:mi mathvariant="normal">Δ</mml:mi></mml:mrow></mml:mrow><mml:msub><mml:mrow><mml:mi>F</mml:mi></mml:mrow><mml:mrow><mml:mrow><mml:mrow><mml:mi mathvariant="normal">b</mml:mi><mml:mi mathvariant="normal">i</mml:mi><mml:mi mathvariant="normal">n</mml:mi><mml:mi mathvariant="normal">d</mml:mi><mml:mo>,</mml:mo><mml:mi mathvariant="normal">r</mml:mi><mml:mi mathvariant="normal">e</mml:mi><mml:mi mathvariant="normal">l</mml:mi></mml:mrow></mml:mrow></mml:mrow></mml:msub><mml:mo>=</mml:mo><mml:mrow><mml:mo stretchy="false">|</mml:mo></mml:mrow><mml:msub><mml:mrow><mml:mrow><mml:mover><mml:mi>F</mml:mi><mml:mo stretchy="false">¯</mml:mo></mml:mover></mml:mrow></mml:mrow><mml:mrow><mml:mrow><mml:mrow><mml:mi mathvariant="normal">b</mml:mi><mml:mi mathvariant="normal">i</mml:mi><mml:mi mathvariant="normal">n</mml:mi><mml:mi mathvariant="normal">d</mml:mi></mml:mrow></mml:mrow><mml:mo>,</mml:mo><mml:mrow><mml:mrow><mml:mi mathvariant="normal">m</mml:mi><mml:mi mathvariant="normal">u</mml:mi><mml:mi mathvariant="normal">t</mml:mi></mml:mrow></mml:mrow></mml:mrow></mml:msub><mml:mo>−</mml:mo><mml:msub><mml:mrow><mml:mrow><mml:mover><mml:mi>F</mml:mi><mml:mo stretchy="false">¯</mml:mo></mml:mover></mml:mrow></mml:mrow><mml:mrow><mml:mrow><mml:mrow><mml:mi mathvariant="normal">b</mml:mi><mml:mi mathvariant="normal">i</mml:mi><mml:mi mathvariant="normal">n</mml:mi><mml:mi mathvariant="normal">d</mml:mi></mml:mrow></mml:mrow><mml:mo>,</mml:mo><mml:mrow><mml:mrow><mml:mi mathvariant="normal">w</mml:mi><mml:mi mathvariant="normal">t</mml:mi></mml:mrow></mml:mrow></mml:mrow></mml:msub><mml:mrow><mml:mo stretchy="false">|</mml:mo></mml:mrow><mml:mrow><mml:mo>/</mml:mo></mml:mrow><mml:mrow><mml:mo stretchy="false">|</mml:mo></mml:mrow><mml:msub><mml:mrow><mml:mrow><mml:mover><mml:mi>F</mml:mi><mml:mo stretchy="false">¯</mml:mo></mml:mover></mml:mrow></mml:mrow><mml:mrow><mml:mrow><mml:mrow><mml:mi mathvariant="normal">b</mml:mi><mml:mi mathvariant="normal">i</mml:mi><mml:mi mathvariant="normal">n</mml:mi><mml:mi mathvariant="normal">d</mml:mi></mml:mrow></mml:mrow><mml:mo>,</mml:mo><mml:mrow><mml:mrow><mml:mi mathvariant="normal">w</mml:mi><mml:mi mathvariant="normal">t</mml:mi></mml:mrow></mml:mrow></mml:mrow></mml:msub><mml:mrow><mml:mo stretchy="false">|</mml:mo></mml:mrow></mml:math><graphic xlink:href="41598_2017_8419_Article_Equ3.gif" position="anchor"></graphic></alternatives></disp-formula>where <inline-formula id="IEq3"><alternatives><tex-math id="M11">\documentclass[12pt]{minimal}
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\begin{document}$${\bar{F}}_{{\rm{bind}},{\rm{mut}}}$$\end{document}</tex-math><mml:math id="M12"><mml:msub><mml:mrow><mml:mover accent="true"><mml:mi>F</mml:mi><mml:mo>¯</mml:mo></mml:mover></mml:mrow><mml:mrow><mml:mi mathvariant="normal">bind</mml:mi><mml:mo>,</mml:mo><mml:mi mathvariant="normal">mut</mml:mi></mml:mrow></mml:msub></mml:math><inline-graphic xlink:href="41598_2017_8419_Article_IEq3.gif"></inline-graphic></alternatives></inline-formula> and <inline-formula id="IEq4"><alternatives><tex-math id="M13">\documentclass[12pt]{minimal}
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\begin{document}$${\bar{F}}_{{\rm{bind}},{\rm{wt}}}$$\end{document}</tex-math><mml:math id="M14"><mml:msub><mml:mrow><mml:mover accent="true"><mml:mi>F</mml:mi><mml:mo>¯</mml:mo></mml:mover></mml:mrow><mml:mrow><mml:mi mathvariant="normal">bind</mml:mi><mml:mo>,</mml:mo><mml:mi mathvariant="normal">wt</mml:mi></mml:mrow></mml:msub></mml:math><inline-graphic xlink:href="41598_2017_8419_Article_IEq4.gif"></inline-graphic></alternatives></inline-formula> are the components of the electrostatic force between the microtubule and the mutant and wild type kinesin in the binding direction, respectively.</p></sec></sec><sec id="Sec6" sec-type="results"><title>Results</title><sec id="Sec7"><title>Electrostatic forces act between kinesin and tubulin</title><p id="Par23">In our previous work, we demonstrated that the electrostatic forces on kinesin-5 form a binding funnel around the tubulin dimer<sup><xref ref-type="bibr" rid="CR58">58</xref></sup>. A similar binding funnel was also found for dynein around the tubulin binding pocket<sup><xref ref-type="bibr" rid="CR61">61</xref></sup>. In this work, we found that the binding funnel is common to kinesins, as shown for kinesin-13 as an example (Fig. <xref rid="Fig1" ref-type="fig">1</xref>), and that the electrostatic force guides the kinesin to the binding pocket of the tubulin. We obtained similar results for the other kinesins (Supplementary Material Table <xref rid="MOESM1" ref-type="media">S1</xref>).<fig id="Fig1"><label>Figure 1</label><caption><p>A funnel of electrostatic binding forces guides kinesin to the binding site on a tubulin dimer. The kinesin-13 structure (yellow) was shifted 20 Å away from its bound position and circled around the tubulin dimer (colored blue for positive surface charge and red for negative surface charge) along a circle with a radius of 40 Å. Every 30 degrees, the electrostatic force on the kinesin was calculated. These forces are represented by arrows (green) with their tail end located at the mass center of the kinesin in the 12 locations around the circle and their lengths proportional to the magnitude of the electrostatic force. (<bold>A</bold>) and (<bold>C</bold>) are the side views. (<bold>B</bold>) and (<bold>D</bold>) are the top views. In (<bold>A</bold>) and (<bold>B</bold>) the kinesin structure is shown at two positions for illustration of the range of displacement. In (<bold>C</bold>) and (<bold>D</bold>) the kinesin is hidden to provide clear view of the forces. In all frames, the total electrostatic forces were calculated using DelPhiForce and visualized with VMD<sup><xref ref-type="bibr" rid="CR76">76</xref></sup>.</p></caption><graphic xlink:href="41598_2017_8419_Fig1_HTML" id="d29e1338"></graphic></fig></p><p id="Par24">Because the electrostatic force is a vector, <inline-formula id="IEq5"><alternatives><tex-math id="M15">\documentclass[12pt]{minimal}
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\begin{document}$$\bar{F}$$\end{document}</tex-math><mml:math id="M16"><mml:mover accent="true"><mml:mi>F</mml:mi><mml:mo>¯</mml:mo></mml:mover></mml:math><inline-graphic xlink:href="41598_2017_8419_Article_IEq5.gif"></inline-graphic></alternatives></inline-formula>, we examined its components in the longitudinal (<italic>F</italic><sub>long</sub>), lateral (<italic>F</italic><sub>lat</sub>), and binding (<italic>F</italic><sub>bind</sub>) directions (Fig. <xref rid="Fig2" ref-type="fig">2</xref>) separately to further assess the role of electrostatic forces. We found that the magnitude of the mean electrostatic force, <inline-formula id="IEq6"><alternatives><tex-math id="M17">\documentclass[12pt]{minimal}
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\begin{document}$$|{\bar{F}}_{{\rm{avg}}}|$$\end{document}</tex-math><mml:math id="M18"><mml:mo stretchy="false">|</mml:mo><mml:mrow><mml:msub><mml:mrow><mml:mover accent="true"><mml:mi>F</mml:mi><mml:mo>¯</mml:mo></mml:mover></mml:mrow><mml:mrow><mml:mi mathvariant="normal">avg</mml:mi></mml:mrow></mml:msub></mml:mrow><mml:mo stretchy="false">|</mml:mo></mml:math><inline-graphic xlink:href="41598_2017_8419_Article_IEq6.gif"></inline-graphic></alternatives></inline-formula>, for the 10 wild type kinesins used in this study in the bound state was 1,450 ± 170 pN (results for each kinesin are shown in Supplemental Material Table <xref rid="MOESM1" ref-type="media">S1</xref>). Preforming the same calculations for unbound kinesins (at a displacement of 5 Å from the tubulin) resulted in an 87% decrease in <inline-formula id="IEq7"><alternatives><tex-math id="M19">\documentclass[12pt]{minimal}
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\begin{document}$$|{\bar{F}}_{{\rm{avg}}}|$$\end{document}</tex-math><mml:math id="M20"><mml:mo stretchy="false">|</mml:mo><mml:mrow><mml:msub><mml:mrow><mml:mover accent="true"><mml:mi>F</mml:mi><mml:mo>¯</mml:mo></mml:mover></mml:mrow><mml:mrow><mml:mi mathvariant="normal">avg</mml:mi></mml:mrow></mml:msub></mml:mrow><mml:mo stretchy="false">|</mml:mo></mml:math><inline-graphic xlink:href="41598_2017_8419_Article_IEq7.gif"></inline-graphic></alternatives></inline-formula> to 192 ± 56 pN. However, despite the large drop in magnitude, the direction of that mean force, and therefore the contribution of individual components, in the bound state was statistically indistinguishable from the unbound state (Table <xref rid="Tab2" ref-type="table">2</xref>). The component of the mean electrostatic force in the binding direction, <italic>F</italic><sub>bind,avg</sub>, contributed the most to the force magnitude (Table <xref rid="Tab2" ref-type="table">2</xref>), and the components in the lateral, <italic>F</italic><sub>lat,avg</sub>, and longitudinal, <italic>F</italic><sub>long,avg</sub>, directions were not statistically different from zero (Table <xref rid="Tab2" ref-type="table">2</xref>).<fig id="Fig2"><label>Figure 2</label><caption><p>Definition of forces components. As an illustrative example, kinesin-3 family member KIF1A (light blue) is shown in the bound state on a tubulin dimer with α-tubulin (red) on the left side and β-tubulin (orange) on the right side. The “longitudinal” direction is along the microtubule, shown (green arrow) positive pointing toward the plus end. The “binding” direction is normal to the surface of the microtubule, shown (green arrow) positive toward the microtubule lumen. The “lateral” direction is around the microtubule, shown (green indicator) coming out of the page toward the reader.</p></caption><graphic xlink:href="41598_2017_8419_Fig2_HTML" id="d29e1463"></graphic></fig><table-wrap id="Tab2"><label>Table 2</label><caption><p>Mean electrostatic force magnitude and direction.</p></caption><table frame="hsides" rules="groups"><thead><tr><th rowspan="2">Kinesin/Tubulin State</th><th rowspan="2">Electrostatic force magnitude (pN)</th><th colspan="3">Components of the unit vector</th></tr><tr><th>Lateral</th><th>Binding</th><th>Longitudinal</th></tr></thead><tbody><tr><td>Bound state</td><td>1450 ± 170</td><td>−0.16 ± 0.17</td><td>0.67 ± 0.08</td><td>0.10 ± 0.15</td></tr><tr><td>Unbound state</td><td>192 ± 56</td><td>−0.15 ± 0.17</td><td>0.77 ± 0.07</td><td>−0.01 ± 0.09</td></tr></tbody></table><table-wrap-foot><p>Note: Values are reported as mean ± standard error of the mean; n = 10 wild type kinesin proteins.</p></table-wrap-foot></table-wrap></p></sec><sec id="Sec8"><title>Electrostatic forces and diseases</title><p id="Par25">We calculated the electrostatic force differences, <inline-formula id="IEq8"><alternatives><tex-math id="M21">\documentclass[12pt]{minimal}
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\begin{document}$${\rm{\Delta }}\bar{F}$$\end{document}</tex-math><mml:math id="M22"><mml:mi mathvariant="normal">Δ</mml:mi><mml:mover accent="true"><mml:mi>F</mml:mi><mml:mo>¯</mml:mo></mml:mover></mml:math><inline-graphic xlink:href="41598_2017_8419_Article_IEq8.gif"></inline-graphic></alternatives></inline-formula> (Equation <xref rid="Equ1" ref-type="">1</xref>), of bound and unbound structures (Supplementary Material Table <xref rid="MOESM1" ref-type="media">S1</xref>), where the force difference quantifies the difference in electrostatic force between the mutant and the corresponding wild type structure. Like the electrostatic force, force differences have three components in the longitudinal (Δ<italic>F</italic><sub>long</sub>), lateral (Δ<italic>F</italic><sub>lat</sub>), and binding (Δ<italic>F</italic><sub>bind</sub>) directions (Fig. <xref rid="Fig2" ref-type="fig">2</xref>). Besides the force differences, we also calculated the relative force difference Δ<italic>F</italic><sub>rel</sub> (Equation <xref rid="Equ2" ref-type="">2</xref>). We found that mutations with larger values of relative force differences, Δ<italic>F</italic><sub>rel</sub>, are more likely to cause disease (Supplementary Material Table <xref rid="MOESM1" ref-type="media">S1</xref>).</p><p id="Par26">We quantified the result that large Δ<italic>F</italic><sub>rel</sub> tends to cause disease using Receiver Operating Characteristic (ROC) plots (Fig. <xref rid="Fig3" ref-type="fig">3</xref>). The area under an ROC plot indicates how well a descriptor, in this case Δ<italic>F</italic><sub>rel</sub>, discriminates between two states, in this case whether a mutation is disease-causing or non-disease-causing. The area under an ROC plot of 1 indicates the descriptor can always discriminate between the states, and the area under a ROC plot of 0.5 (corresponding to the red dotted line in Fig. <xref rid="Fig3" ref-type="fig">3</xref>) indicates the descriptor is no better than random chance.<fig id="Fig3"><label>Figure 3</label><caption><p>Magnitude of the electrostatic force difference, Δ<italic>F</italic><sub>rel</sub>, can be used to predict whether a mutation is disease-causing. ROC plots are of Δ<italic>F</italic><sub>rel</sub> calculated in the bound state (BS Mag, black line), the component of force difference in the binding direction, Δ<italic>F</italic><sub>bind,rel</sub>, in the bound state (BS BC, blue line), Δ<italic>F</italic><sub>rel</sub> in the unbound (UBS Mag, red line), and Δ<italic>F</italic><sub>bind,rel</sub> in the unbound state (UBS BC, green line). The areas below these four ROC curves are: 0.79, 0.77, 0.84, 0.84, respectively.</p></caption><graphic xlink:href="41598_2017_8419_Fig3_HTML" id="d29e1663"></graphic></fig></p><p id="Par27">We found that Δ<italic>F</italic><sub>rel</sub> of unbound structures provided a better prediction of disease than Δ<italic>F</italic><sub>rel</sub> of bound structures because the areas under the unbound state ROC plots were 0.84 and 0.84 for Δ<italic>F</italic><sub>rel</sub> and Δ<italic>F</italic><sub>bind,rel</sub>, respectively (Fig. <xref rid="Fig3" ref-type="fig">3</xref>) and the area under the bound state ROC plots were 0.79 and 0.77 for Δ<italic>F</italic><sub>rel</sub> and Δ<italic>F</italic><sub>bind,rel</sub>, respectively (Fig. <xref rid="Fig3" ref-type="fig">3</xref>). We also noted that Δ<italic>F</italic><sub>rel</sub> performed slightly better than Δ<italic>F</italic><sub>bind,rel</sub> for structures in bound states (Fig. <xref rid="Fig3" ref-type="fig">3</xref>). We obtained similar results from ROC plots (Supplementary Material Figure <xref rid="MOESM2" ref-type="media">S1</xref>) of electrostatic force calculations at an ionic strength of 0.15 M, indicating that ionic strength does not play a role in discriminating disease-causing from non-disease-causing mutations. Thus, in the rest of the manuscript, we focus on results obtained with I = 0 M. Since disease can be caused by either decreasing or increasing the wild type force, we did ROC using the absolute values of <inline-formula id="IEq9"><alternatives><tex-math id="M23">\documentclass[12pt]{minimal}
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\begin{document}$$|{\rm{\Delta }}\bar{F}|$$\end{document}</tex-math><mml:math id="M24"><mml:mo stretchy="true">|</mml:mo><mml:mrow><mml:mi mathvariant="normal">Δ</mml:mi><mml:mover accent="true"><mml:mi>F</mml:mi><mml:mo>¯</mml:mo></mml:mover></mml:mrow><mml:mo stretchy="true">|</mml:mo></mml:math><inline-graphic xlink:href="41598_2017_8419_Article_IEq9.gif"></inline-graphic></alternatives></inline-formula> and |Δ<italic>F</italic><sub>bind</sub>|, for both unbound and bound states, which resulted in similar as above performance; areas under ROC curve ranged from 0.72 to 0.75 (Supplementary Material Figure <xref rid="MOESM2" ref-type="media">S2</xref>).</p></sec><sec id="Sec9"><title>Statistical analysis of electrostatic force components and disease-causing mutations</title><p id="Par28">We further investigated the unbound state’s <inline-formula id="IEq10"><alternatives><tex-math id="M25">\documentclass[12pt]{minimal}
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\begin{document}$$|{\rm{\Delta }}\bar{F}|\,\,$$\end{document}</tex-math><mml:math id="M26"><mml:mrow><mml:mo stretchy="true">|</mml:mo><mml:mrow><mml:mi mathvariant="normal">Δ</mml:mi><mml:mover accent="true"><mml:mi>F</mml:mi><mml:mo>¯</mml:mo></mml:mover></mml:mrow><mml:mo stretchy="true">|</mml:mo></mml:mrow><mml:mspace width=".25em"></mml:mspace><mml:mspace width=".25em"></mml:mspace></mml:math><inline-graphic xlink:href="41598_2017_8419_Article_IEq10.gif"></inline-graphic></alternatives></inline-formula>and its <inline-formula id="IEq11"><alternatives><tex-math id="M27">\documentclass[12pt]{minimal}
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\begin{document}$${\rm{\Delta }}\bar{F}$$\end{document}</tex-math><mml:math id="M28"><mml:mi mathvariant="normal">Δ</mml:mi><mml:mover accent="true"><mml:mi>F</mml:mi><mml:mo>¯</mml:mo></mml:mover></mml:math><inline-graphic xlink:href="41598_2017_8419_Article_IEq11.gif"></inline-graphic></alternatives></inline-formula>’s components as predictors of whether a mutation is disease-causing or non-disease-causing using histograms (Fig. <xref rid="Fig4" ref-type="fig">4</xref>). We found that all mutations in our study with <inline-formula id="IEq12"><alternatives><tex-math id="M29">\documentclass[12pt]{minimal}
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\begin{document}$$|{\rm{\Delta }}\bar{F}| > 16$$\end{document}</tex-math><mml:math id="M30"><mml:mrow><mml:mo stretchy="true">|</mml:mo><mml:mrow><mml:mi mathvariant="normal">Δ</mml:mi><mml:mover accent="true"><mml:mi>F</mml:mi><mml:mo>¯</mml:mo></mml:mover></mml:mrow><mml:mo stretchy="true">|</mml:mo></mml:mrow><mml:mo>></mml:mo><mml:mn>16</mml:mn></mml:math><inline-graphic xlink:href="41598_2017_8419_Article_IEq12.gif"></inline-graphic></alternatives></inline-formula> pN led to disease and that only 9% of the non-disease causing mutations had <inline-formula id="IEq13"><alternatives><tex-math id="M31">\documentclass[12pt]{minimal}
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\begin{document}$$|{\rm{\Delta }}\bar{F}| > 4$$\end{document}</tex-math><mml:math id="M32"><mml:mrow><mml:mo stretchy="true">|</mml:mo><mml:mrow><mml:mi mathvariant="normal">Δ</mml:mi><mml:mover accent="true"><mml:mi>F</mml:mi><mml:mo>¯</mml:mo></mml:mover></mml:mrow><mml:mo stretchy="true">|</mml:mo></mml:mrow><mml:mo>></mml:mo><mml:mn>4</mml:mn></mml:math><inline-graphic xlink:href="41598_2017_8419_Article_IEq13.gif"></inline-graphic></alternatives></inline-formula> pN (Fig. <xref rid="Fig4" ref-type="fig">4A</xref>).<fig id="Fig4"><label>Figure 4</label><caption><p>Whether a mutation causes a disease or not is correlated to the electrostatic force differences. Normalized histograms of disease-causing (black) and non-disease-causing (gray) mutations by electrostatic force difference when kinesin is in the unbound state for (<bold>A</bold>) <inline-formula id="IEq14"><alternatives><tex-math id="M33">\documentclass[12pt]{minimal}
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\begin{document}$$|{\rm{\Delta }}\bar{F}|$$\end{document}</tex-math><mml:math id="M34"><mml:mo stretchy="true">|</mml:mo><mml:mrow><mml:mi mathvariant="normal">Δ</mml:mi><mml:mover accent="true"><mml:mi>F</mml:mi><mml:mo>¯</mml:mo></mml:mover></mml:mrow><mml:mo stretchy="true">|</mml:mo></mml:math><inline-graphic xlink:href="41598_2017_8419_Article_IEq14.gif"></inline-graphic></alternatives></inline-formula>, (<bold>B</bold>) Δ<italic>F</italic><sub>bind</sub>, (<bold>C</bold>) Δ<italic>F</italic><sub>lat</sub>, and (<bold>D</bold>) Δ<italic>F</italic><sub>long</sub>. Total mutation counts are labeled on each bar. Note that our dataset included a total of 50 disease-causing mutants and 11 non-disease-causing mutants. The error bars indicate the standard deviation.</p></caption><graphic xlink:href="41598_2017_8419_Fig4_HTML" id="d29e1919"></graphic></fig></p><p id="Par29">We also found that kinesins had a higher tolerance to Δ<italic>F</italic><sub>bind</sub> and Δ<italic>F</italic><sub>long</sub> than to Δ<italic>F</italic><sub>lat</sub>. We found that only 9% of the non-disease-causing mutants had Δ<italic>F</italic><sub>lat</sub> > 1 pN while 36% had Δ<italic>F</italic><sub>bind</sub> > 1 pN and 27% had Δ<italic>F</italic><sub>long</sub> > 1 pN (Fig. <xref rid="Fig4" ref-type="fig">4B,C,D</xref>). We also noted that mutations causing Δ<italic>F</italic><sub>lat</sub> between 1 pN and 4 pN did a much better job distinguishing disease state because this range in Δ<italic>F</italic><sub>lat</sub> contains 35% of all disease-causing but only 9% of non-disease-causing mutants, which is statistically significantly different (<italic>p</italic>-value = 0.02), but this same range in Δ<italic>F</italic><sub>bind</sub> and Δ<italic>F</italic><sub>long</sub> had percentages of disease-causing and non-disease-causing that were statistically indistinguishable (Fig. <xref rid="Fig4" ref-type="fig">4B,C,D</xref>).</p></sec><sec id="Sec10"><title>Analysis of additional features that may be used to discriminate disease-causing and non-disease-causing mutations</title><p id="Par30">We performed a statistical analysis of 23 features potentially affecting the pathogenicity of kinesin mutations using standard techniques (see Supplementary Material). By comparing the <italic>p</italic>-values of an F-regression analysis, we found that electrostatic force was the best predictor (Table <xref rid="Tab3" ref-type="table">3</xref>). The other good predictors were the secondary structure of mutation position, change in binding free energy, and the location of mutation site (Table <xref rid="Tab3" ref-type="table">3</xref>). The buried surface area, residue polarity, residue charge, etc., were not identified as significant features in predicting pathogenicity (Table <xref rid="Tab3" ref-type="table">3</xref>).<table-wrap id="Tab3"><label>Table 3</label><caption><p>Statistical analysis of 23 possible features.</p></caption><table frame="hsides" rules="groups"><thead><tr><th><italic>Numerical Features</italic></th><th><italic>p</italic>-value in f Regression</th><th>f Regression Score</th></tr></thead><tbody><tr><td>Difference in total force at 5 Å distance</td><td>0.02</td><td>5.33</td></tr><tr><td>Absolute difference in binding force at 5 Å distance</td><td>0.03</td><td>5.19</td></tr><tr><td>Absolute difference in longitudinal force at 5 Å distance</td><td>0.06</td><td>3.68</td></tr><tr><td>Absolute difference in lateral force at 5 Å distance</td><td>0.07</td><td>3.40</td></tr><tr><td>Change in charge</td><td>0.12</td><td>2.51</td></tr><tr><td>Change in binding free energy</td><td>0.13</td><td>2.38</td></tr><tr><td>Change in buried surface area</td><td>0.23</td><td>1.49</td></tr><tr><td>Absolute difference in longitudinal force at bound state</td><td>0.24</td><td>1.42</td></tr><tr><td>Difference in total force at bound state</td><td>0.25</td><td>1.34</td></tr><tr><td>Absolute difference in longitudinal force at bound state</td><td>0.25</td><td>1.34</td></tr><tr><td>Absolute difference in binding force at bound state</td><td>0.28</td><td>1.18</td></tr><tr><td>Absolute difference in lateral force at bound state</td><td>0.30</td><td>1.09</td></tr><tr><td>Difference in longitudinal force at bound state</td><td>0.35</td><td>0.90</td></tr><tr><td>Difference in binding force at bound state</td><td>0.39</td><td>0.74</td></tr><tr><td>Change in folding free energy</td><td>0.40</td><td>0.71</td></tr><tr><td>Difference in lateral force at bound state</td><td>0.47</td><td>0.53</td></tr><tr><td>Difference in binding force at 5 Å Distance</td><td>0.57</td><td>0.33</td></tr><tr><td>Difference in lateral force at 5 Å Distance</td><td>0.60</td><td>0.28</td></tr><tr><td>Difference in longitudinal force at 5 Å Distance</td><td>0.69</td><td>0.16</td></tr><tr><td><bold><italic>Categorical Features</italic></bold></td><td><bold>Logistic Regression Coefficient</bold></td><td></td></tr><tr><td>Change in polarity</td><td>0.46</td><td></td></tr><tr><td>Residue on binding site</td><td>−0.01</td><td></td></tr><tr><td>Residue exposure</td><td>−0.08</td><td></td></tr><tr><td>Secondary structure of mutation residue</td><td>−0.23</td><td></td></tr></tbody></table></table-wrap></p><p id="Par31">We found that 88% of the disease-causing mutations occur in α-helices, coils, and turns (Fig. <xref rid="Fig5" ref-type="fig">5A</xref>). Only 31% of mutations located on strands caused disease, which is significantly fewer than the 61% and 53% disease-causing rates for mutations on coils and turns, respectively (Fig. <xref rid="Fig5" ref-type="fig">5A</xref>). Our data had few instances of mutations on 3–10 helices or salt bridges, therefore these mutations are not taken into further analysis.<fig id="Fig5"><label>Figure 5</label><caption><p>Location of the mutation is correlated to its likelihood of causing disease. (<bold>A</bold>) Histograms indicating which secondary structure the mutated residue is on for disease-causing and non-disease-causing mutants. (<bold>B</bold>) Histograms indicating whether the mutated residue is on the microtubule binding interface or not for disease-causing and non-disease-causing mutants.</p></caption><graphic xlink:href="41598_2017_8419_Fig5_HTML" id="d29e2302"></graphic></fig></p><p id="Par32">Additionally, we noted that the disease-causing nature of a mutation was correlated to the function of the structure domain upon which it resides. 76% of mutations at the tubulin binding site were disease-causing (Fig. <xref rid="Fig5" ref-type="fig">5B</xref>), while mutations at other locations were disease-causing in only 46% of instances (Fig. <xref rid="Fig5" ref-type="fig">5B</xref>). Note that since this study focused on the kinesin-tubulin interaction, mutations on ATP binding site were not taken into further discussion.</p></sec></sec><sec id="Sec11" sec-type="discussion"><title>Discussion</title><p id="Par33">We demonstrated that the changes of the electrostatic component of the force between kinesin and microtubule caused by amino acid mutations in the kinesin motor domain serve as a good discriminator between disease-causing and non-disease-causing mutations. 23 other features typically used by the computational community were also investigated, but we found them to be not as good predictors of disease state as the change of the electrostatic force. These results are remarkable because kinesin-related diseases may originate from nsSNPs causing effects within the motor domain not related to kinesin-microtubule binding. These effects may include disruption of nucleotide hydrolysis site because motility requires ATP hydrolysis<sup><xref ref-type="bibr" rid="CR62">62</xref></sup>, proximity of the mutation to the location neck-linker-motor domain interaction site because motility requires neck linker docking<sup><xref ref-type="bibr" rid="CR63">63</xref>, <xref ref-type="bibr" rid="CR64">64</xref></sup>, and motor domain structural stability because structure and function are closely correlated in structured proteins. Additionally, the kinesin family to which the mutated protein belongs could also be an important factor because certain families may have more critical cell or developmental biological function than others, and certain families may have fewer functional redundancies with other motors within the family than others<sup><xref ref-type="bibr" rid="CR65">65</xref></sup>. Moreover, that our results show electrostatic force is a good discriminator between disease-causing and non-disease causing mutations suggests that there is steep electrostatic potential energy well about the kinesin docking location on the microtubule. Because the force is proportional to the spatial gradient of potential energy, small changes in the electrostatic energy potential result in large change in the force. Therefore, it is likely that electrostatic force is an even better discriminator than electrostatic energy potential.</p><p id="Par34">We checked if our results were biased by the location of the mutations sites relative to the kinesin-microtubule binding interface by generating a representative kinesin motor domain-tubulin structure (Fig. <xref rid="Fig6" ref-type="fig">6</xref>). We note that the kinesin motor domains studied in this work have similar structures (Fig. <xref rid="Fig6" ref-type="fig">6A</xref>), and thus we use one (kinesin-3) to visualize the location of mutations sites (Fig. <xref rid="Fig6" ref-type="fig">6B</xref>). We found that there is no preference for disease-causing mutations to be at the binding interface while non-disease-causing mutations are away.<fig id="Fig6"><label>Figure 6</label><caption><p>Mutations distribution map. (<bold>A</bold>) The structural alignment for all the kinesin-tubulin dimer structures studied, each color representing a different kinesin structure. (<bold>B</bold>) Mutations sites mapped on a representative kinesin structure (kinesin-3 family member, KIF1A). Red residues indicate disease-causing mutation sites and yellow residues indicate non-disease-causing mutation sites. α-tubulin (red) is on the left and β-tubulin (orange) is on the right in both panels.</p></caption><graphic xlink:href="41598_2017_8419_Fig6_HTML" id="d29e2357"></graphic></fig></p><p id="Par35">Recent studies indicate that positively charged residues on the kinesin motor domain strengthens its interaction with the microtubule, while negatively charged residues have an opposite effect<sup><xref ref-type="bibr" rid="CR22">22</xref>, <xref ref-type="bibr" rid="CR23">23</xref>, <xref ref-type="bibr" rid="CR25">25</xref>, <xref ref-type="bibr" rid="CR66">66</xref></sup>. Consistent with these previous studies, we have found that most of the disease-causing mutations we studied involve charged residues. Our findings provide additional evidence for the importance of charged residues and electrostatics to kinesin motor domain microtubule binding. Furthermore, we found that Y274 and L248, which were previously identified as the top two most important uncharged residues for kinesin-microtubule binding<sup><xref ref-type="bibr" rid="CR22">22</xref>, <xref ref-type="bibr" rid="CR66">66</xref></sup>, were also associated with disease-causing mutations in kinesin-3 family member KIF1A (L249Q) and in kinesin-1 family member KIF5A (Y276C). The correspondence between important previously identified charged and uncharged residues<sup><xref ref-type="bibr" rid="CR22">22</xref>, <xref ref-type="bibr" rid="CR66">66</xref></sup> and disease-association allows us to speculate that mutations at other positions identified as important in previous studies<sup><xref ref-type="bibr" rid="CR22">22</xref>, <xref ref-type="bibr" rid="CR66">66</xref></sup> including R346, K44, and K261, which do not appear in our database, are likely to be disease-causing.</p><p id="Par36">Our key result is that if a mutation causes a <inline-formula id="IEq15"><alternatives><tex-math id="M35">\documentclass[12pt]{minimal}
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\begin{document}$$|{\rm{\Delta }}\bar{F}| > 4$$\end{document}</tex-math><mml:math id="M36"><mml:mrow><mml:mo stretchy="true">|</mml:mo><mml:mrow><mml:mi mathvariant="normal">Δ</mml:mi><mml:mover accent="true"><mml:mi>F</mml:mi><mml:mo>¯</mml:mo></mml:mover></mml:mrow><mml:mo stretchy="true">|</mml:mo></mml:mrow><mml:mo>></mml:mo><mml:mn>4</mml:mn></mml:math><inline-graphic xlink:href="41598_2017_8419_Article_IEq15.gif"></inline-graphic></alternatives></inline-formula> pN in the unbound state, then it is very likely to cause disease. Such a threshold roughly corresponds to 1 kcal/mol binding energy, an energy threshold that is widely used to discriminate disease-causing from non-disease-causing mutations<sup><xref ref-type="bibr" rid="CR67">67</xref></sup>. Below we investigate a few particular mutants more closely, as illustrative examples, to understand our result a bit better.</p><p id="Par37">First, we noted that kinesin-3 family member KIF1A E253K is charge reversal, from a negatively charged glutamic acid residue to a positively charged lysine residue, and it resulted in the largest <inline-formula id="IEq16"><alternatives><tex-math id="M37">\documentclass[12pt]{minimal}
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\begin{document}$$|{\rm{\Delta }}\bar{F}|$$\end{document}</tex-math><mml:math id="M38"><mml:mo stretchy="true">|</mml:mo><mml:mrow><mml:mi mathvariant="normal">Δ</mml:mi><mml:mover accent="true"><mml:mi>F</mml:mi><mml:mo>¯</mml:mo></mml:mover></mml:mrow><mml:mo stretchy="true">|</mml:mo></mml:math><inline-graphic xlink:href="41598_2017_8419_Article_IEq16.gif"></inline-graphic></alternatives></inline-formula> (Supplementary Material Table <xref rid="MOESM1" ref-type="media">S1</xref>) in both the bound and unbound states. We looked carefully at the magnitude and direction of the force on each amino acid in this kinesin-3 (Fig. <xref rid="Fig7" ref-type="fig">7</xref>). We found that the mutated amino acid lies close to the tubulin interface: the distance between the CA atom of E253 and the closest CA atom on tubulin is 9.6 Å. Because the mutation flips the charge of the residue and it is so close to the highly-charged tubulin interface, the large change in force we calculated was likely do the negative-to-positive charge reversal. The negatively charged E253 in wild type kinesin-3 opposes binding (Fig. <xref rid="Fig7" ref-type="fig">7</xref> red arrow), and the positively charged K253 in the mutant kinesin-3 favors binding (Fig. <xref rid="Fig7" ref-type="fig">7</xref> blue arrow), to the net negatively charged tubulin dimer. It is therefore not surprising that the enhanced binding due to this mutation causes spastic paraparesis and sensory and autonomic neuropathy type-2<sup><xref ref-type="bibr" rid="CR39">39</xref></sup> given that kinesin-3 drives long-distance transport in neuronal cells<sup><xref ref-type="bibr" rid="CR9">9</xref></sup>.<fig id="Fig7"><label>Figure 7</label><caption><p>Forces on each residue of kinesin-3 show the large change in relative force due to the mutation. Kinesin-3 family member KIF1A (light blue) with the E253K mutation is shown bound to a tubulin dimer with α-tubulin (red) on the left side and β-tubulin (orange) on the right side. Most electrostatic forces (yellow arrows) on each residue of the kinesin-3 remain unchanged, but the force on residue 253 changes with the mutation, with both the force on wild type (red arrow) and the force on the mutant (blue arrow) shown.</p></caption><graphic xlink:href="41598_2017_8419_Fig7_HTML" id="d29e2477"></graphic></fig></p><p id="Par38">Second, we noted that kinesin-8 family member KIF18A T273A mutant is the only non-disease causing mutant with a <inline-formula id="IEq17"><alternatives><tex-math id="M39">\documentclass[12pt]{minimal}
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\begin{document}$$|{\rm{\Delta }}\bar{F}| > 4$$\end{document}</tex-math><mml:math id="M40"><mml:mrow><mml:mo stretchy="true">|</mml:mo><mml:mrow><mml:mi mathvariant="normal">Δ</mml:mi><mml:mover accent="true"><mml:mi>F</mml:mi><mml:mo>¯</mml:mo></mml:mover></mml:mrow><mml:mo stretchy="true">|</mml:mo></mml:mrow><mml:mo>></mml:mo><mml:mn>4</mml:mn></mml:math><inline-graphic xlink:href="41598_2017_8419_Article_IEq17.gif"></inline-graphic></alternatives></inline-formula> pN; it had <inline-formula id="IEq18"><alternatives><tex-math id="M41">\documentclass[12pt]{minimal}
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\begin{document}$$|{\rm{\Delta }}\bar{F}|=4.92$$\end{document}</tex-math><mml:math id="M42"><mml:mrow><mml:mo stretchy="true">|</mml:mo><mml:mrow><mml:mi mathvariant="normal">Δ</mml:mi><mml:mover accent="true"><mml:mi>F</mml:mi><mml:mo>¯</mml:mo></mml:mover></mml:mrow><mml:mo stretchy="true">|</mml:mo></mml:mrow><mml:mo>=</mml:mo><mml:mn>4.92</mml:mn></mml:math><inline-graphic xlink:href="41598_2017_8419_Article_IEq18.gif"></inline-graphic></alternatives></inline-formula> pN. We looked carefully at the location of this residue in the structure and found it to reside on an unstructured region (or at least one that is not in the PDB ID 3LRE structure)<sup><xref ref-type="bibr" rid="CR68">68</xref></sup> on the microtubule binding surface<sup><xref ref-type="bibr" rid="CR22">22</xref></sup>, thus leading to a relatively large calculated <inline-formula id="IEq19"><alternatives><tex-math id="M43">\documentclass[12pt]{minimal}
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\begin{document}$$|{\rm{\Delta }}\bar{F}|$$\end{document}</tex-math><mml:math id="M44"><mml:mo stretchy="true">|</mml:mo><mml:mrow><mml:mi mathvariant="normal">Δ</mml:mi><mml:mover accent="true"><mml:mi>F</mml:mi><mml:mo>¯</mml:mo></mml:mover></mml:mrow><mml:mo stretchy="true">|</mml:mo></mml:math><inline-graphic xlink:href="41598_2017_8419_Article_IEq19.gif"></inline-graphic></alternatives></inline-formula>. However, the T273 is not highly conserved and the T273A does not change the motility of the kinesin in <italic>in vitro</italic> motility assays<sup><xref ref-type="bibr" rid="CR22">22</xref></sup>. This could explain how this mutation is non-disease-causing despite relatively large <inline-formula id="IEq20"><alternatives><tex-math id="M45">\documentclass[12pt]{minimal}
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\begin{document}$$|{\rm{\Delta }}\bar{F}|$$\end{document}</tex-math><mml:math id="M46"><mml:mo stretchy="true">|</mml:mo><mml:mrow><mml:mi mathvariant="normal">Δ</mml:mi><mml:mover accent="true"><mml:mi>F</mml:mi><mml:mo>¯</mml:mo></mml:mover></mml:mrow><mml:mo stretchy="true">|</mml:mo></mml:math><inline-graphic xlink:href="41598_2017_8419_Article_IEq20.gif"></inline-graphic></alternatives></inline-formula>.</p><p id="Par39">Third, we noted that the kinesin-1 family member KIF5A S203C mutant has a low <inline-formula id="IEq21"><alternatives><tex-math id="M47">\documentclass[12pt]{minimal}
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\begin{document}$$|{\rm{\Delta }}\bar{F}|=1.27$$\end{document}</tex-math><mml:math id="M48"><mml:mrow><mml:mo stretchy="true">|</mml:mo><mml:mrow><mml:mi mathvariant="normal">Δ</mml:mi><mml:mover accent="true"><mml:mi>F</mml:mi><mml:mo>¯</mml:mo></mml:mover></mml:mrow><mml:mo stretchy="true">|</mml:mo></mml:mrow><mml:mo>=</mml:mo><mml:mn>1.27</mml:mn></mml:math><inline-graphic xlink:href="41598_2017_8419_Article_IEq21.gif"></inline-graphic></alternatives></inline-formula> pN in the unbound state (Supplementary Material Table <xref rid="MOESM1" ref-type="media">S1</xref>), well below the discrimination threshold of 4 pN, but is disease-causing. We looked carefully at the location of this mutation, and found it is located in close proximity (5.5 Å) to the Mg<sup>2+</sup> ion in the nucleotide binding site<sup><xref ref-type="bibr" rid="CR69">69</xref></sup>. Specifically, S203 resides within a highly conserved sequence (NXXSSR, residues 199–204 of KIF5A) in switch I<sup><xref ref-type="bibr" rid="CR30">30</xref></sup>, and it is thought to be important in recognizing the hydrolysis state of bound the nucleotide<sup><xref ref-type="bibr" rid="CR70">70</xref></sup>. This could explain how this mutation causes a disease despite low <inline-formula id="IEq22"><alternatives><tex-math id="M49">\documentclass[12pt]{minimal}
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\begin{document}$$|{\rm{\Delta }}\bar{F}|$$\end{document}</tex-math><mml:math id="M50"><mml:mo stretchy="true">|</mml:mo><mml:mrow><mml:mi mathvariant="normal">Δ</mml:mi><mml:mover accent="true"><mml:mi>F</mml:mi><mml:mo>¯</mml:mo></mml:mover></mml:mrow><mml:mo stretchy="true">|</mml:mo></mml:math><inline-graphic xlink:href="41598_2017_8419_Article_IEq22.gif"></inline-graphic></alternatives></inline-formula>, highlighting our discrimination method’s limitation in finding all the true positive cases, particularly when mutations are unrelated to the kinesin-tubulin interaction.</p><p id="Par40">While we did find that <inline-formula id="IEq23"><alternatives><tex-math id="M51">\documentclass[12pt]{minimal}
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\begin{document}$$|{\rm{\Delta }}\bar{F}| > 4$$\end{document}</tex-math><mml:math id="M52"><mml:mrow><mml:mo stretchy="true">|</mml:mo><mml:mrow><mml:mi mathvariant="normal">Δ</mml:mi><mml:mover accent="true"><mml:mi>F</mml:mi><mml:mo>¯</mml:mo></mml:mover></mml:mrow><mml:mo stretchy="true">|</mml:mo></mml:mrow><mml:mo>></mml:mo><mml:mn>4</mml:mn></mml:math><inline-graphic xlink:href="41598_2017_8419_Article_IEq23.gif"></inline-graphic></alternatives></inline-formula> pN in the unbound state is an excellent discriminator, we also found that the three components of the relative force difference, Δ<italic>F</italic><sub>long,rel</sub>, Δ<italic>F</italic><sub>lat,rel</sub>, and Δ<italic>F</italic><sub>bind,rel</sub>, are also successful predictors, in their own right. These results suggest that the individual components of the binding force, particularly the lateral and longitudinal components, may be of critical importance for kinesin motility. It should be additionally noted that the magnitude of the electrostatic force is significantly (least 5-fold) larger in the binding direction than the other two directions (Table <xref rid="Tab1" ref-type="table">1</xref>). Thus, it is likely to be less sensitive to the changes in magnitude than the other directions. If a mutation changes the force in the binding direction a given amount, kinesin may still bind to tubulin properly, however if the force in the lateral or longitudinal direction were changed by that same amount, it may be significantly more sensitive to the difference. It should be noted that the absolute value of the electrostatic force change was found to be the best discriminator. Thus, mutations strengthening the binding are equally likely to be disease-causing as mutations weakening it. This is consistent with previous studies on other systems, indicating that these systems are optimized and any deviation away from the wild type properties could be disease-causing<sup><xref ref-type="bibr" rid="CR4">4</xref>, <xref ref-type="bibr" rid="CR67">67</xref></sup>.</p><p id="Par41">Finally, it should be noted that this study considers the electrostatic component of the force acting between the kinesin and tubulin, not the total force. A kinesin motor domain that is not subjected to other external force, e.g. a cargo load, is at equilibrium on the microtubule. Therefore, at equilibrium, non-electrostatic forces must be acting at the tubulin-kinesin interface to balance out the large magnitude electrostatic forces we have calculated.</p></sec><sec sec-type="supplementary-material"><title>Electronic supplementary material</title><sec id="Sec12"><p><supplementary-material content-type="local-data" id="MOESM1"><media xlink:href="41598_2017_8419_MOESM1_ESM.xlsx"><caption><p>Table 1S</p></caption></media></supplementary-material><supplementary-material content-type="local-data" id="MOESM2"><media xlink:href="41598_2017_8419_MOESM2_ESM.pdf"><caption><p>Supplementary Information</p></caption></media></supplementary-material></p></sec></sec></body><back><fn-group><fn><p>Lin Li and Zhe Jia contributed equally to this work.</p></fn><fn><p><bold>Electronic supplementary material</bold></p><p><bold>Supplementary information</bold> accompanies this paper at doi:10.1038/s41598-017-08419-7
</p></fn><fn><p><bold>Publisher's note:</bold> Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.</p></fn></fn-group><ack><title>Acknowledgements</title><p>The work of L.L., Z.J., Y.P., I.G. and E.A. was supported by a grant from the Institute of General Medical Sciences, National Institutes of Health, award number R01GM093937.</p></ack><notes notes-type="author-contribution"><title>Author Contributions</title><p>L.L. and Z.J. designed the research, analyzed the data and drafted the manuscript. 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