Expanding molecular modeling and design tools to non-natural sidechains.

Détails

ID Serval
serval:BIB_7B7B0EDE9303
Type
Article: article d'un périodique ou d'un magazine.
Collection
Publications
Titre
Expanding molecular modeling and design tools to non-natural sidechains.
Périodique
Journal of Computational Chemistry
Auteur(s)
Gfeller D., Michielin O., Zoete V.
ISSN
1096-987X (Electronic)
ISSN-L
0192-8651
Statut éditorial
Publié
Date de publication
2012
Volume
33
Numéro
18
Pages
1525-1535
Langue
anglais
Résumé
Protein-protein interactions encode the wiring diagram of cellular signaling pathways and their deregulations underlie a variety of diseases, such as cancer. Inhibiting protein-protein interactions with peptide derivatives is a promising way to develop new biological and therapeutic tools. Here, we develop a general framework to computationally handle hundreds of non-natural amino acid sidechains and predict the effect of inserting them into peptides or proteins. We first generate all structural files (pdb and mol2), as well as parameters and topologies for standard molecular mechanics software (CHARMM and Gromacs). Accurate predictions of rotamer probabilities are provided using a novel combined knowledge and physics based strategy. Non-natural sidechains are useful to increase peptide ligand binding affinity. Our results obtained on non-natural mutants of a BCL9 peptide targeting beta-catenin show very good correlation between predicted and experimental binding free-energies, indicating that such predictions can be used to design new inhibitors. Data generated in this work, as well as PyMOL and UCSF Chimera plug-ins for user-friendly visualization of non-natural sidechains, are all available at http://www.swisssidechain.ch. Our results enable researchers to rapidly and efficiently work with hundreds of non-natural sidechains.
Mots-clé
Amino Acids/chemistry, Computer Simulation, Drug Design, Molecular Structure, Protein Binding, Proteins/chemistry, Thermodynamics
Pubmed
Web of science
Création de la notice
29/06/2012 18:28
Dernière modification de la notice
03/03/2018 18:35
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