Computational design of D-peptide inhibitors of hepatitis delta antigen dimerization.
Identifieur interne : 000077 ( Ncbi/Checkpoint ); précédent : 000076; suivant : 000078Computational design of D-peptide inhibitors of hepatitis delta antigen dimerization.
Auteurs : C D Elkin [États-Unis] ; H J Zuccola ; J M Hogle ; D. Joseph-MccarthySource :
- Journal of computer-aided molecular design [ 0920-654X ] ; 2000.
Descripteurs français
- KwdFr :
- MESH :
English descriptors
- KwdEn :
- MESH :
- chemical , chemistry : Antiviral Agents, Hepatitis Antigens.
- chemical , pharmacology : Antiviral Agents.
- drug effects : Hepatitis Delta Virus.
- immunology : Hepatitis Delta Virus.
- Algorithms, Amino Acid Sequence, Database Management Systems, Dimerization, Protein Conformation.
Abstract
Hepatitis delta virus (HDV) encodes a single polypeptide called hepatitis delta antigen (DAg). Dimerization of DAg is required for viral replication. The structure of the dimerization region, residues 12 to 60, consists of an anti-parallel coiled coil [Zuccola et al., Structure, 6(1998)821]. Multiple Copy Simultaneous Searches (MCSS) of the hydrophobic core region formed by the bend in the helix of one monomer of this structure were carried out for many diverse functional groups. Six critical interaction sites were identified. The Protein Data Bank was searched for backbone templates to use in the subsequent design process by matching to these sites. A 14 residue helix expected to bind to the D-isomer of the target structure was selected as the template. Over 200,000 mutant sequences of this peptide were generated based on the MCSS results. A secondary structure prediction algorithm was used to screen all sequences. and in general only those that were predicted to be highly helical were retained. Approximately 100 of these 14-mers were model built as D-peptides and docked with the L-isomer of the target monomer. Based on calculated interaction energies, predicted helicity, and intrahelical salt bridge patterns, a small number of peptides were selected as the most promising candidates. The ligand design approach presented here is the computational analogue of mirror image phage display. The results have been used to characterize the interactions responsible for formation of this model anti-parallel coiled coil and to suggest potential ligands to disrupt it.
DOI: 10.1023/a:1008146015629
PubMed: 11131965
Affiliations:
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pubmed:11131965Le document en format XML
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<front><div type="abstract" xml:lang="en">Hepatitis delta virus (HDV) encodes a single polypeptide called hepatitis delta antigen (DAg). Dimerization of DAg is required for viral replication. The structure of the dimerization region, residues 12 to 60, consists of an anti-parallel coiled coil [Zuccola et al., Structure, 6(1998)821]. Multiple Copy Simultaneous Searches (MCSS) of the hydrophobic core region formed by the bend in the helix of one monomer of this structure were carried out for many diverse functional groups. Six critical interaction sites were identified. The Protein Data Bank was searched for backbone templates to use in the subsequent design process by matching to these sites. A 14 residue helix expected to bind to the D-isomer of the target structure was selected as the template. Over 200,000 mutant sequences of this peptide were generated based on the MCSS results. A secondary structure prediction algorithm was used to screen all sequences. and in general only those that were predicted to be highly helical were retained. Approximately 100 of these 14-mers were model built as D-peptides and docked with the L-isomer of the target monomer. Based on calculated interaction energies, predicted helicity, and intrahelical salt bridge patterns, a small number of peptides were selected as the most promising candidates. The ligand design approach presented here is the computational analogue of mirror image phage display. The results have been used to characterize the interactions responsible for formation of this model anti-parallel coiled coil and to suggest potential ligands to disrupt it.</div>
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