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Molecular dynamics study of the proposed β‐hairpin form of the switch domain from HIV1 gp120 alone and complexed with an inhibitor of CD4 binding
Author(s) -
Graf von Stosch Andreas,
von der Lieth C.W.,
Reed Jennifer
Publication year - 1999
Publication title -
proteins: structure, function, and bioinformatics
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.699
H-Index - 191
eISSN - 1097-0134
pISSN - 0887-3585
DOI - 10.1002/(sici)1097-0134(19990201)34:2<197::aid-prot5>3.0.co;2-#
Subject(s) - chemistry , circular dichroism , peptide , molecular dynamics , folding (dsp implementation) , side chain , binding site , stereochemistry , biophysics , biochemistry , computational chemistry , biology , organic chemistry , electrical engineering , engineering , polymer
The strong tendency of β‐hairpin peptides to aggregate can prevent their structural resolution. The polar form of the switch peptide (LAV 15mer) at the CD4‐binding domain of HIV1 gp120 is such a peptide, and NMR investigations of its interaction with a class of CD4‐binding inhibitors developed in this laboratory have been hindered. Detailed knowledge of the interaction is required for the development of more potent switch inhibitors, that act by disrupting the cooperative folding transition necessary for binding to the CD4 receptor. In carrying out molecular dynamics simulation of the free peptide under polar conditions, we found that the properties of the resulting structure agree closely with those observed by circular dichroism. The same conditions, used to model the peptide/inhibitor complex, produced a stable bimolecular structure with specific interactions between the inhibitor and side chains on the peptide, (e.g., Trp 12 and the LPCR tetrad), known to control the folding transition. These help explain existing data on the relative potency of inhibitor derivatives and provide a basis for improved inhibitor design. Proteins 1999;34:197–205. © 1999 Wiley‐Liss, Inc.