期刊
JOURNAL OF CHEMICAL THEORY AND COMPUTATION
卷 10, 期 12, 页码 5696-5705出版社
AMER CHEMICAL SOC
DOI: 10.1021/ct500584n
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资金
- National Institutes of Health [NIH-GM4330]
- National Science Foundation [NSF-CHE-0910943, OCI-1053575]
Computer simulations are used to determine the free energy landscape for the binding of the anticancer drug Dasatinib to its src kinase receptor and show that before settling into a free energy basin the ligand must surmount a free energy barrier. An analysis based on using both the ligand-pocket separation and the pocket-water occupancy as reaction coordinates shows that the free energy barrier is a result of the free energy cost for almost complete desolvation of the binding pocket. The simulations further show that the barrier is not a result of the reorganization free energy of the binding pocket. Although a continuum solvent model gives the location of free energy minima, it is not able to reproduce the intermediate free energy barrier. Finally, it is shown that a kinetic model for the on rate constant in which the ligand diffuses up to a doorway state and then surmounts the desolvation free energy barrier is consistent with published microsecond time-scale simulations of the ligand binding kinetics for this system [Shaw, D. E. et al. J. Am. Chem. Soc. 2011, 133, 9181-9183].
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