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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 ligand approach tothe bindingpocket of kinase in the absence of restraint on the pocket (originalresult) with that in the presence of restraint on the pocket.
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fig7: Comparison of free energy profile of ligand approach tothe bindingpocket of kinase in the absence of restraint on the pocket (originalresult) with that in the presence of restraint on the pocket.

Mentions: One might wonder how much the reorganization of thepocket contributes to the intermediate barrier seen in the PMF. Toinvestigate this, we have repeated the computation of the PMF usingposition restraints on each of the atoms in the binding pocket inorder to prevent the pocket from reorganizing. In Figure 7, a similar intermediate free energy barrier appearseven when reorganization of the pocket is restrained suggesting thatthis intermediate barrier does not result from pocket reorganization.Interestingly, the free energy of the binding pose is lower for restrainedpocket than for the unrestrained pocket probably because there isless steric hindrance to the ligand. In addition we also have foundthat the radius of gyration of the binding pocket increases at mostby a few angstroms when the ligand is moved from bulk solution tothe position of the intermediate free energy barrier, a change thatis not significant. Therefore, we believe that the major contributionto the intermediate free energy barrier comes from the free energyof desolvation and not from reorganization of the pocket.


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 ligand approach tothe bindingpocket of kinase in the absence of restraint on the pocket (originalresult) with that in the presence of restraint on the pocket.
© Copyright Policy
Related In: Results  -  Collection

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

fig7: Comparison of free energy profile of ligand approach tothe bindingpocket of kinase in the absence of restraint on the pocket (originalresult) with that in the presence of restraint on the pocket.
Mentions: One might wonder how much the reorganization of thepocket contributes to the intermediate barrier seen in the PMF. Toinvestigate this, we have repeated the computation of the PMF usingposition restraints on each of the atoms in the binding pocket inorder to prevent the pocket from reorganizing. In Figure 7, a similar intermediate free energy barrier appearseven when reorganization of the pocket is restrained suggesting thatthis intermediate barrier does not result from pocket reorganization.Interestingly, the free energy of the binding pose is lower for restrainedpocket than for the unrestrained pocket probably because there isless steric hindrance to the ligand. In addition we also have foundthat the radius of gyration of the binding pocket increases at mostby a few angstroms when the ligand is moved from bulk solution tothe position of the intermediate free energy barrier, a change thatis not significant. Therefore, we believe that the major contributionto the intermediate free energy barrier comes from the free energyof desolvation and not from reorganization of the pocket.

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