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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

Comparison of free energy profile of ligandapproach to the bindingpocket of kinase in implicit solvent with that in explicit water.
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fig8: Comparison of free energy profile of ligandapproach to the bindingpocket of kinase in implicit solvent with that in explicit water.

Mentions: We suspect that continuumsolvation models will not be able to account for the intermediatefree energy barrier if this barrier is due, as we claim, to desolvation,because such models cannot account for desolvation accurately whenan atomic level description of individual water molecules, sensitiveto the size of the particles, is important. Many popular existingdrug-binding scoring functions like MM/GBSA or MM/PBSA are based onimplicit solvent models. We repeated the computation of the PMF usinga popular continuum solvent model GBSA.34,35 Figure 8 compares the PMFs for GBSA with that of explicitwater. We find that although the position of the well correspondingto the binding pose is essentially the same for GBSA and explicitwater, GBSA does not predict the intermediate free energy barrier,as we suspected, and also overstabilizes the overall ligand binding.The result is reminiscent of a previous study by Mondal et al.46 where the implicit solvent description of freeenergy of association of a pair of beta-peptides was found to be overstabilizedcompared to that of explicit solvent simulation, even though therewas agreement in the location of free-energy minima. In an earlierstudy, Berne and co-workers47 also foundthat the continuum solvent description of a free energy landscapeof the hairpin part of G-protein overweights many non-native configurations.Thefree energy profile in implicit solvent has been verified againstindependent runs (Figure S5 of the SupportingInformation).


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

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

Comparison of free energy profile of ligandapproach to the bindingpocket of kinase in implicit solvent with that in explicit water.
© Copyright Policy
Related In: Results  -  Collection

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

fig8: Comparison of free energy profile of ligandapproach to the bindingpocket of kinase in implicit solvent with that in explicit water.
Mentions: We suspect that continuumsolvation models will not be able to account for the intermediatefree energy barrier if this barrier is due, as we claim, to desolvation,because such models cannot account for desolvation accurately whenan atomic level description of individual water molecules, sensitiveto the size of the particles, is important. Many popular existingdrug-binding scoring functions like MM/GBSA or MM/PBSA are based onimplicit solvent models. We repeated the computation of the PMF usinga popular continuum solvent model GBSA.34,35 Figure 8 compares the PMFs for GBSA with that of explicitwater. We find that although the position of the well correspondingto the binding pose is essentially the same for GBSA and explicitwater, GBSA does not predict the intermediate free energy barrier,as we suspected, and also overstabilizes the overall ligand binding.The result is reminiscent of a previous study by Mondal et al.46 where the implicit solvent description of freeenergy of association of a pair of beta-peptides was found to be overstabilizedcompared to that of explicit solvent simulation, even though therewas agreement in the location of free-energy minima. In an earlierstudy, Berne and co-workers47 also foundthat the continuum solvent description of a free energy landscapeof the hairpin part of G-protein overweights many non-native configurations.Thefree energy profile in implicit solvent has been verified againstindependent runs (Figure S5 of the SupportingInformation).

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