title: Role of Desolvation in Thermodynamics and Kinetics of Ligand Binding to a Kinase.
abstract: 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].
authors.affiliation: Department of Chemistry, Columbia University , 3000 Broadway, New York, New York 10027, United States.
authors.forename: Jagannath
authors.initials: J
authors.lastname: Mondal
authors.affiliation: Department of Chemistry, Columbia University , 3000 Broadway, New York, New York 10027, United States.
authors.forename: Richard A
authors.initials: RA
authors.lastname: Friesner
authors.affiliation: Department of Chemistry, Columbia University , 3000 Broadway, New York, New York 10027, United States.
authors.forename: B J
authors.initials: BJ
authors.lastname: Berne