This article was published online on 14 April 2012. An error was subsequently identified. This notice is included in the online and print versions to indicate that both have been corrected 24 April 2012.
Expanding molecular modeling and design tools to non-natural sidechains†
Article first published online: 14 APR 2012
Copyright © 2012 Wiley Periodicals, Inc.
Journal of Computational Chemistry
Volume 33, Issue 18, pages 1525–1535, 5 July 2012
How to Cite
Gfeller, D., Michielin, O. and Zoete, V. (2012), Expanding molecular modeling and design tools to non-natural sidechains. J. Comput. Chem., 33: 1525–1535. doi: 10.1002/jcc.22982
- Issue published online: 4 JUN 2012
- Article first published online: 14 APR 2012
- Manuscript Accepted: 10 MAR 2012
- Manuscript Revised: 7 FEB 2012
- Manuscript Received: 17 NOV 2011
- non-natural sidechain;
- molecular modeling;
- drug design
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. © 2012 Wiley Periodicals, Inc.