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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

a) Representative snapshot of Dasatinib (silver color) in its nativebinding pocket (purple color) of kinase. The density map of the nativebinding pocket has been obtained by averaging over frames of trajectory.Only part of the proteins has been shown (in ribbon representation),and water and ions are not shown for clarity. b) The chemical structureof the ligand Dasatinib used in the work (identical to that providedin ref (16)).
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fig1: a) Representative snapshot of Dasatinib (silver color) in its nativebinding pocket (purple color) of kinase. The density map of the nativebinding pocket has been obtained by averaging over frames of trajectory.Only part of the proteins has been shown (in ribbon representation),and water and ions are not shown for clarity. b) The chemical structureof the ligand Dasatinib used in the work (identical to that providedin ref (16)).

Mentions: In order to obtain physicalinsight and useful semiquantitativeinformation concerning the barriers to ligand binding and unbinding,in this paper we analyze how the free-energy changes as the ligandapproaches its binding pose. We explore the binding of a FDA-approvedkinase-inhibitor Dasatinib14−16 to src-kinase,17 the same kinase and ligand studied by Shaw and co-workers.A representative snapshot of Dasatinib in its native binding posein the pocket of kinase is shown in Figure 1 a. In the present work, we take a different approach. In particularwe explore the role played by explicit water molecules in the bindingprocess with a focus on the free energy of pocket desolvation. Usingmolecular dynamics and free energy simulation methods we show thatthe ligand encounters a free-energy barrier just prior to reachingits binding pose. By treating both the water-occupancyand the ligand-pocket separation distance as reaction coordinates,we quantitatively trace the origin of this barrier to the displacementof pocket-waters by the ligand en route to its binding. In addition,application of the WaterMap technique6 helpsto clarify our findings by characterizing the thermodynamic natureof pocket-waters at various ligand-pocket distances. As expected,application of a continuum solvent model (GBSA) fails to find thefree energy barrier as implicit solvent models ignore explicit solvation.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 surmountsthe desolvation free energy barrier, is consistent with the Shaw group’svery long simulations of the ligand binding kinetics for this system.


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

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

a) Representative snapshot of Dasatinib (silver color) in its nativebinding pocket (purple color) of kinase. The density map of the nativebinding pocket has been obtained by averaging over frames of trajectory.Only part of the proteins has been shown (in ribbon representation),and water and ions are not shown for clarity. b) The chemical structureof the ligand Dasatinib used in the work (identical to that providedin ref (16)).
© Copyright Policy
Related In: Results  -  Collection

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

fig1: a) Representative snapshot of Dasatinib (silver color) in its nativebinding pocket (purple color) of kinase. The density map of the nativebinding pocket has been obtained by averaging over frames of trajectory.Only part of the proteins has been shown (in ribbon representation),and water and ions are not shown for clarity. b) The chemical structureof the ligand Dasatinib used in the work (identical to that providedin ref (16)).
Mentions: In order to obtain physicalinsight and useful semiquantitativeinformation concerning the barriers to ligand binding and unbinding,in this paper we analyze how the free-energy changes as the ligandapproaches its binding pose. We explore the binding of a FDA-approvedkinase-inhibitor Dasatinib14−16 to src-kinase,17 the same kinase and ligand studied by Shaw and co-workers.A representative snapshot of Dasatinib in its native binding posein the pocket of kinase is shown in Figure 1 a. In the present work, we take a different approach. In particularwe explore the role played by explicit water molecules in the bindingprocess with a focus on the free energy of pocket desolvation. Usingmolecular dynamics and free energy simulation methods we show thatthe ligand encounters a free-energy barrier just prior to reachingits binding pose. By treating both the water-occupancyand the ligand-pocket separation distance as reaction coordinates,we quantitatively trace the origin of this barrier to the displacementof pocket-waters by the ligand en route to its binding. In addition,application of the WaterMap technique6 helpsto clarify our findings by characterizing the thermodynamic natureof pocket-waters at various ligand-pocket distances. As expected,application of a continuum solvent model (GBSA) fails to find thefree energy barrier as implicit solvent models ignore explicit solvation.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 surmountsthe desolvation free energy barrier, is consistent with the Shaw group’svery long simulations of the ligand binding kinetics for this system.

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