期刊
JOURNAL OF COMPUTATIONAL CHEMISTRY
卷 33, 期 18, 页码 1525-1535出版社
WILEY
DOI: 10.1002/jcc.22982
关键词
non-natural sidechain; rotamer; peptide; molecular modeling; drug design
资金
- EMBO
Proteinprotein interactions encode the wiring diagram of cellular signaling pathways and their deregulations underlie a variety of diseases, such as cancer. Inhibiting proteinprotein 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 . Our results enable researchers to rapidly and efficiently work with hundreds of non-natural sidechains. (C) 2012 Wiley Periodicals, Inc.
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