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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

Representativesnapshots of pocket-water at ligand-pocket distancescorresponding to d = 0.95 and 0.75 nm. The averagedensity map of the binding pocket is shown in pink, the waters areshown in blue color with space-filling representation, and the ligandis shown in silver color with licorice representation.
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fig4: Representativesnapshots of pocket-water at ligand-pocket distancescorresponding to d = 0.95 and 0.75 nm. The averagedensity map of the binding pocket is shown in pink, the waters areshown in blue color with space-filling representation, and the ligandis shown in silver color with licorice representation.

Mentions: The contribution of desolvationto large binding affinities in other complexes has been explored before.6,41,45 We investigate the desolvationof the binding pocket on ligand approach and determine its contributionto the free energy. Figure 3 (right-hand scale)shows that the number of water molecules present in the kinase bindingpocket as a function of d first decreases from 6,when the ligand is out of the pocket, to 3, when it is at the barrier,to essentially zero, right after it passes the barrier, and then increasesslightly as some water molecules reenter the pocket when the ligandtakes up its binding pose. Figure 4 shows representativesnapshots (which are also similar to final snapshots of each windows)of the distribution of water before and after the ligand overcomesthe barrier.


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

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

Representativesnapshots of pocket-water at ligand-pocket distancescorresponding to d = 0.95 and 0.75 nm. The averagedensity map of the binding pocket is shown in pink, the waters areshown in blue color with space-filling representation, and the ligandis shown in silver color with licorice representation.
© Copyright Policy
Related In: Results  -  Collection

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

fig4: Representativesnapshots of pocket-water at ligand-pocket distancescorresponding to d = 0.95 and 0.75 nm. The averagedensity map of the binding pocket is shown in pink, the waters areshown in blue color with space-filling representation, and the ligandis shown in silver color with licorice representation.
Mentions: The contribution of desolvationto large binding affinities in other complexes has been explored before.6,41,45 We investigate the desolvationof the binding pocket on ligand approach and determine its contributionto the free energy. Figure 3 (right-hand scale)shows that the number of water molecules present in the kinase bindingpocket as a function of d first decreases from 6,when the ligand is out of the pocket, to 3, when it is at the barrier,to essentially zero, right after it passes the barrier, and then increasesslightly as some water molecules reenter the pocket when the ligandtakes up its binding pose. Figure 4 shows representativesnapshots (which are also similar to final snapshots of each windows)of the distribution of water before and after the ligand overcomesthe barrier.

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