Binding free energy differences in a TCR-peptide-MHC complex induced by a peptide mutation: a simulation analysis.

Détails

ID Serval
serval:BIB_ECD8D7AD7694
Type
Article: article d'un périodique ou d'un magazine.
Collection
Publications
Institution
Titre
Binding free energy differences in a TCR-peptide-MHC complex induced by a peptide mutation: a simulation analysis.
Périodique
Journal of molecular biology
Auteur⸱e⸱s
Michielin O., Karplus M.
ISSN
0022-2836
Statut éditorial
Publié
Date de publication
2002
Peer-reviewed
Oui
Volume
324
Numéro
3
Pages
547-569
Langue
anglais
Notes
Publication types: Journal Article ; Research Support, Non-U.S. Gov't - Publication Status: ppublish
Résumé
Recognition by the T-cell receptor (TCR) of immunogenic peptides presented by class I major histocompatibility complexes (MHCs) is the determining event in the specific cellular immune response against virus-infected cells or tumor cells. It is of great interest, therefore, to elucidate the molecular principles upon which the selectivity of a TCR is based. These principles can in turn be used to design therapeutic approaches, such as peptide-based immunotherapies of cancer. In this study, free energy simulation methods are used to analyze the binding free energy difference of a particular TCR (A6) for a wild-type peptide (Tax) and a mutant peptide (Tax P6A), both presented in HLA A2. The computed free energy difference is 2.9 kcal/mol, in good agreement with the experimental value. This makes possible the use of the simulation results for obtaining an understanding of the origin of the free energy difference which was not available from the experimental results. A free energy component analysis makes possible the decomposition of the free energy difference between the binding of the wild-type and mutant peptide into its components. Of particular interest is the fact that better solvation of the mutant peptide when bound to the MHC molecule is an important contribution to the greater affinity of the TCR for the latter. The results make possible identification of the residues of the TCR which are important for the selectivity. This provides an understanding of the molecular principles that govern the recognition. The possibility of using free energy simulations in designing peptide derivatives for cancer immunotherapy is briefly discussed.
Mots-clé
Algorithms, Computer Simulation, Crystallography, X-Ray, Energy Metabolism, HLA-A2 Antigen, Histocompatibility Antigens Class I, Models, Molecular, Mutation, Peptide Fragments, Receptors, Antigen, T-Cell, Static Electricity, Structural Homology, Protein, Thermodynamics
Pubmed
Web of science
Création de la notice
28/01/2008 11:22
Dernière modification de la notice
20/08/2019 16:14
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