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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

Snapshot from WaterMapanalysis showing principal hydration sitesnear the binding pocket before overcoming the free energy barrier(corresponding to d = 0.95 nm) and after overcomingthe barrier (corresponding to d = 0.75 nm).
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fig6: Snapshot from WaterMapanalysis showing principal hydration sitesnear the binding pocket before overcoming the free energy barrier(corresponding to d = 0.95 nm) and after overcomingthe barrier (corresponding to d = 0.75 nm).

Mentions: We explore the possibility of using the recentlydeveloped WaterMap method6 to determinethe position and approximate magnitude of the free energy barrier,by analyzing the hydration of the pocket at two different pocket-liganddistances d, right before (d = 0.95nm) and right after (d = 0.75 nm) the ligand overcomesthe barrier. If successful, this method would provide a relativelyinexpensive way to predict the position and magnitude of the barrierarising from desolvation. The WaterMap method predicts regions ofhigh-water density (referred to as ’hydration sites”)and rank-orders them based on the relative free-energies of the water-clusters.The two WaterMap snapshots depicted in Figure 6 represent the principal hydration sites before and after the ligandovercomes the free energy barrier, respectively.


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

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

Snapshot from WaterMapanalysis showing principal hydration sitesnear the binding pocket before overcoming the free energy barrier(corresponding to d = 0.95 nm) and after overcomingthe barrier (corresponding to d = 0.75 nm).
© Copyright Policy
Related In: Results  -  Collection

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

fig6: Snapshot from WaterMapanalysis showing principal hydration sitesnear the binding pocket before overcoming the free energy barrier(corresponding to d = 0.95 nm) and after overcomingthe barrier (corresponding to d = 0.75 nm).
Mentions: We explore the possibility of using the recentlydeveloped WaterMap method6 to determinethe position and approximate magnitude of the free energy barrier,by analyzing the hydration of the pocket at two different pocket-liganddistances d, right before (d = 0.95nm) and right after (d = 0.75 nm) the ligand overcomesthe barrier. If successful, this method would provide a relativelyinexpensive way to predict the position and magnitude of the barrierarising from desolvation. The WaterMap method predicts regions ofhigh-water density (referred to as ’hydration sites”)and rank-orders them based on the relative free-energies of the water-clusters.The two WaterMap snapshots depicted in Figure 6 represent the principal hydration sites before and after the ligandovercomes the free energy barrier, respectively.

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