期刊
JOURNAL OF CHEMICAL PHYSICS
卷 137, 期 23, 页码 -出版社
AMER INST PHYSICS
DOI: 10.1063/1.4769292
关键词
biochemistry; drugs; free energy; molecular biophysics; proteins
资金
- National Institutes of Health [1R15GM096257-01A1]
- Louisiana Board of Regents Research Competitiveness and Research Enhancement Subprograms
- Louisiana Optical Network Initiative
- Louisiana Board of Regents Post-Katrina Support Fund Initiative Grant [LEQSF(2007-12)-ENH-PKSFI-PRS-01]
- National Science Foundation under NSF EPSCoR [EPS-1003897]
- Louisiana Board of Regents
Computational techniques see widespread use in pharmaceutical drug discovery, but typically prove unreliable in predicting trends in protein-ligand binding. Alchemical free energy calculations seek to change that by providing rigorous binding free energies from molecular simulations. Given adequate sampling and an accurate enough force field, these techniques yield accurate free energy estimates. Recent innovations in alchemical techniques have sparked a resurgence of interest in these calculations. Still, many obstacles stand in the way of their routine application in a drug discovery context, including the one we focus on here, sampling. Sampling of binding modes poses a particular challenge as binding modes are often separated by large energy barriers, leading to slow transitions. Binding modes are difficult to predict, and in some cases multiple binding modes may contribute to binding. In view of these hurdles, we present a framework for dealing carefully with uncertainty in binding mode or conformation in the context of free energy calculations. With careful sampling, free energy techniques show considerable promise for aiding drug discovery. (C) 2012 American Institute of Physics. [http://dx.doi.org/10.1063/1.4769292]
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