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 th

SUBMITTER: Mondal J 

PROVIDER: S-EPMC4263462 | biostudies-literature | 2014 Dec

REPOSITORIES: biostudies-literature