Free energy landscapes for initiation and branching of protein aggregation
Identifieur interne : 000406 ( Pmc/Corpus ); précédent : 000405; suivant : 000407Free energy landscapes for initiation and branching of protein aggregation
Auteurs : Weihua Zheng ; Nicholas P. Schafer ; Peter G. WolynesSource :
- Proceedings of the National Academy of Sciences of the United States of America [ 0027-8424 ] ; 2013.
Abstract
This study leverages a predictive protein-folding simulation model to study the free energy landscapes of fused oligomeric constructs to quantify the conditions under which these constructs spontaneously misfold. Constructs of this type have been used to probe the early stages of aggregation in the laboratory. Oligomeric species may be the toxic agents in misfolding-related diseases. The critical structures that initiate aggregation are shown to depend on specific sequence signals and thermodynamic conditions. Our results also suggest that branching due to the presence of multiple amyloidogenic segments may determine the morphology of protein aggregates.
Url:
DOI: 10.1073/pnas.1320483110
PubMed: 24284165
PubMed Central: 3870682
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<front><journal-meta><journal-id journal-id-type="nlm-ta">Proc Natl Acad Sci U S A</journal-id><journal-id journal-id-type="iso-abbrev">Proc. Natl. Acad. Sci. U.S.A</journal-id><journal-id journal-id-type="hwp">pnas</journal-id><journal-id journal-id-type="pmc">pnas</journal-id><journal-id journal-id-type="publisher-id">PNAS</journal-id><journal-title-group><journal-title>Proceedings of the National Academy of Sciences of the United States of America</journal-title></journal-title-group><issn pub-type="ppub">0027-8424</issn><issn pub-type="epub">1091-6490</issn><publisher><publisher-name>National Academy of Sciences</publisher-name></publisher></journal-meta><article-meta><article-id pub-id-type="pmid">24284165</article-id><article-id pub-id-type="pmc">3870682</article-id><article-id pub-id-type="publisher-id">201320483</article-id><article-id pub-id-type="doi">10.1073/pnas.1320483110</article-id><article-categories><subj-group subj-group-type="heading"><subject>Biological Sciences</subject><subj-group><subject>Biophysics and Computational Biology</subject></subj-group></subj-group></article-categories><title-group><article-title>Free energy landscapes for initiation and branching of protein aggregation</article-title><alt-title alt-title-type="short">Initiation and branching of protein aggregation</alt-title></title-group><contrib-group><contrib contrib-type="author"><name><surname>Zheng</surname><given-names>Weihua</given-names></name><xref ref-type="aff" rid="aff1"><sup>a</sup></xref><xref ref-type="aff" rid="aff2"><sup>b</sup></xref></contrib><contrib contrib-type="author"><name><surname>Schafer</surname><given-names>Nicholas P.</given-names></name><xref ref-type="aff" rid="aff2"><sup>b</sup></xref><xref ref-type="aff" rid="aff3"><sup>c</sup></xref></contrib><contrib contrib-type="author"><name><surname>Wolynes</surname><given-names>Peter G.</given-names></name><xref ref-type="aff" rid="aff1"><sup>a</sup></xref><xref ref-type="aff" rid="aff2"><sup>b</sup></xref><xref ref-type="aff" rid="aff3"><sup>c</sup></xref><xref ref-type="corresp" rid="cor1"><sup>1</sup></xref></contrib><aff id="aff1">Departments of<sup>a</sup>Chemistry and</aff><aff id="aff2"><sup>b</sup>Physics and Astronomy, and</aff><aff id="aff3"><sup>c</sup>Center for Theoretical Biological Physics,<institution>Rice University</institution>, Houston,<addr-line>TX</addr-line> 77005</aff></contrib-group><author-notes><corresp id="cor1"><sup>1</sup>To whom correspondence should be addressed. E-mail: <email>pwolynes@rice.edu</email>.</corresp><fn fn-type="edited-by"><p>Contributed by Peter G. Wolynes, October 31, 2013 (sent for review October 10, 2013)</p></fn><fn fn-type="con"><p>Author contributions: W.Z., N.P.S., and P.G.W. designed research; W.Z. and N.P.S. performed research; W.Z. and N.P.S. analyzed data; and W.Z., N.P.S., and P.G.W. wrote the paper.</p></fn></author-notes><pub-date pub-type="ppub"><day>17</day><month>12</month><year>2013</year></pub-date><pub-date pub-type="epub"><day>27</day><month>11</month><year>2013</year></pub-date><volume>110</volume><issue>51</issue><fpage>20515</fpage><lpage>20520</lpage><self-uri xlink:title="pdf" xlink:type="simple" xlink:href="pnas.201320483.pdf"></self-uri><abstract abstract-type="executive-summary"><title>Significance</title><p>This study leverages a predictive protein-folding simulation model to study the free energy landscapes of fused oligomeric constructs to quantify the conditions under which these constructs spontaneously misfold. Constructs of this type have been used to probe the early stages of aggregation in the laboratory. Oligomeric species may be the toxic agents in misfolding-related diseases. The critical structures that initiate aggregation are shown to depend on specific sequence signals and thermodynamic conditions. Our results also suggest that branching due to the presence of multiple amyloidogenic segments may determine the morphology of protein aggregates.</p></abstract><abstract><p>Experiments on artificial multidomain protein constructs have probed the early stages of aggregation processes, but structural details of the species that initiate aggregation remain elusive. Using the associative-memory, water-mediated, structure and energy model known as AWSEM, a transferable coarse-grained protein model, we performed simulations of fused constructs composed of up to four copies of the Titin I27 domain or its mutant I27* (I59E). Free energy calculations enable us to quantify the conditions under which such multidomain constructs will spontaneously misfold. Consistent with experimental results, the dimer of I27 is found to be the smallest spontaneously misfolding construct. Our results show how structurally distinct misfolded states can be stabilized under different thermodynamic conditions, and this result provides a plausible link between the single-molecule misfolding experiments under native conditions and aggregation experiments under denaturing conditions. The conditions for spontaneous misfolding are determined by the interplay among temperature, effective local protein concentration, and the strength of the interdomain interactions. Above the folding temperature, fusing additional domains to the monomer destabilizes the native state, and the entropically stabilized amyloid-like state is favored. Because it is primarily energetically stabilized, the domain-swapped state is more likely to be important under native conditions. Both protofibril-like and branching structures are found in annealing simulations starting from extended structures, and these structures suggest a possible connection between the existence of multiple amyloidogenic segments in each domain and the formation of branched, amorphous aggregates as opposed to linear fibrillar structures.</p></abstract><kwd-group><kwd>energy landscape theory</kwd><kwd>branched aggregates</kwd><kwd>gelation</kwd></kwd-group><counts><page-count count="6"></page-count></counts></article-meta></front></pmc></record>Pour manipuler ce document sous Unix (Dilib)
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