Limits...
Role of Desolvation in Thermodynamics and Kinetics of Ligand Binding to a Kinase.

Mondal J, Friesner RA, Berne BJ - J Chem Theory Comput (2014)

Bottom Line: The simulations further show that the barrier is not a result of the reorganization free energy of the binding pocket.Chem.Soc.2011, 133, 9181-9183].

View Article: PubMed Central - PubMed

Affiliation: Department of Chemistry, Columbia University , 3000 Broadway, New York, New York 10027, United States.

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].

No MeSH data available.


Related in: MedlinePlus

Schematic ofpotential energy surface corresponding to this kineticscheme. kf and εf‡ are the rate constant and corresponding activation barrier for thetransition from the doorway state to the final binding pose. kd′ and εd‡ are the rateconstant and activation barrier for the dissociation of the doorwaycomplex into free ligand and protein. kd is the diffusion controlled rate constant for theligand and protein to diffuse to the doorway state.
© Copyright Policy
Related In: Results  -  Collection

License
getmorefigures.php?uid=PMC4263462&req=5

fig9: Schematic ofpotential energy surface corresponding to this kineticscheme. kf and εf‡ are the rate constant and corresponding activation barrier for thetransition from the doorway state to the final binding pose. kd′ and εd‡ are the rateconstant and activation barrier for the dissociation of the doorwaycomplex into free ligand and protein. kd is the diffusion controlled rate constant for theligand and protein to diffuse to the doorway state.

Mentions: Consider the following simple kinetic scheme for this binding processand its associated schematic free energy diagrampresented in Figure 9.


Role of Desolvation in Thermodynamics and Kinetics of Ligand Binding to a Kinase.

Mondal J, Friesner RA, Berne BJ - J Chem Theory Comput (2014)

Schematic ofpotential energy surface corresponding to this kineticscheme. kf and εf‡ are the rate constant and corresponding activation barrier for thetransition from the doorway state to the final binding pose. kd′ and εd‡ are the rateconstant and activation barrier for the dissociation of the doorwaycomplex into free ligand and protein. kd is the diffusion controlled rate constant for theligand and protein to diffuse to the doorway state.
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4263462&req=5

fig9: Schematic ofpotential energy surface corresponding to this kineticscheme. kf and εf‡ are the rate constant and corresponding activation barrier for thetransition from the doorway state to the final binding pose. kd′ and εd‡ are the rateconstant and activation barrier for the dissociation of the doorwaycomplex into free ligand and protein. kd is the diffusion controlled rate constant for theligand and protein to diffuse to the doorway state.
Mentions: Consider the following simple kinetic scheme for this binding processand its associated schematic free energy diagrampresented in Figure 9.

Bottom Line: The simulations further show that the barrier is not a result of the reorganization free energy of the binding pocket.Chem.Soc.2011, 133, 9181-9183].

View Article: PubMed Central - PubMed

Affiliation: Department of Chemistry, Columbia University , 3000 Broadway, New York, New York 10027, United States.

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].

No MeSH data available.


Related in: MedlinePlus