How inaccuracies in protein structure models affect estimates of protein-ligand interactions: computational analysis of HIV-I protease inhibitor binding.

Détails

ID Serval
serval:BIB_570EC702E08D
Type
Article: article d'un périodique ou d'un magazine.
Collection
Publications
Institution
Titre
How inaccuracies in protein structure models affect estimates of protein-ligand interactions: computational analysis of HIV-I protease inhibitor binding.
Périodique
Proteins
Auteur(s)
Thorsteinsdottir H.B., Schwede T., Zoete V., Meuwly M.
ISSN
1097-0134 (Electronic)
ISSN-L
0887-3585
Statut éditorial
Publié
Date de publication
01/11/2006
Peer-reviewed
Oui
Volume
65
Numéro
2
Pages
407-423
Langue
anglais
Notes
Publication types: Journal Article ; Research Support, Non-U.S. Gov't
Publication Status: ppublish
Résumé
The influence of possible inaccuracies that can arise during homology modeling of protein structures used for ligand binding studies were investigated with the molecular mechanics generalized Born surface area (MM-GBSA) method. For this, a family of well-characterized HIV-I protease-inhibitor complexes was used. Validation of MM-GBSA led to a correlation coefficient ranging from 0.72 to 0.93 between calculated and experimental binding free energies DeltaG. All calculated DeltaG values were based on molecular dynamics simulations with explicit solvent. Errors introduced into the protein structure through misplacement of side-chains during rotamer modeling led to a correlation coefficient between DeltaG(calc) and DeltaG(exp) of 0.75 compared with 0.90 for the correctly placed side chains. This is in contrast to homology models for members of the retroviral protease family with template structures ranging in sequence identity between 32% and 51%. For these protein models, the correlation coefficients vary between 0.84 and 0.87, which is considerably closer to the original protein (0.90). It is concluded that HIV-I low sequence identity with the template structure still allows creating sufficiently reliable homology models to be used for ligand-binding studies, although placement of the rotamers is a critical step during the modeling.

Mots-clé
Amino Acid Sequence, Computer Simulation, HIV Protease/chemistry, HIV Protease/metabolism, HIV Protease Inhibitors/chemistry, HIV Protease Inhibitors/metabolism, HIV-1/enzymology, Ligands, Models, Molecular, Molecular Sequence Data, Molecular Structure, Protein Binding, Sequence Alignment, Sequence Homology, Amino Acid, Thermodynamics
Pubmed
Web of science
Création de la notice
05/02/2018 14:59
Dernière modification de la notice
21/08/2019 5:37
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