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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.


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Comparison performance of the coarse-grained representation ofwater-number to reproduce time-profile of actual number of water.
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fig2: Comparison performance of the coarse-grained representation ofwater-number to reproduce time-profile of actual number of water.

Mentions: Umbrellasampling with d constrained is straightforward, butconstraining the number of pocket-water requires some ingenuity asdescribed in the literature where the number of water molecules N in the pocket is approximated by a continuous function.39−41 Based on an analysis of the pair-correlation function of water moleculeswith respect to the position of the center-of-mass of the pocket,we count all water molecules within an effective cutoff distance r0 = 0.5 nm of the center of mass of the pocketas “pocket water molecules”. We then take the coarse-grainedwater occupancy number N in the pocket to bewhere r is the distance ofthe oxygen atom of each water molecule from center of mass position, rcom, of the binding pocket,that is r = /rW – rcom/, andthe summation runs over all water molecules in the simulation box.As shown in Figure 2, this coarse-grained representationof the water occupation number reproduces the time profile of ‘atomistic‘water number reasonably well and makes it possible to apply restraintsto bias the pocket-water occupancy in an umbrella sampling simulationof the water occupancy number. With this definition, the pocket wateroccupancy is a continuous variable that adopts noninteger values,and its corresponding probability distribution P(N) (and free energy G(N) = −kBT ln P(N)) becomes a continuous function.


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 performance of the coarse-grained representation ofwater-number to reproduce time-profile of actual number of water.
© Copyright Policy
Related In: Results  -  Collection

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

fig2: Comparison performance of the coarse-grained representation ofwater-number to reproduce time-profile of actual number of water.
Mentions: Umbrellasampling with d constrained is straightforward, butconstraining the number of pocket-water requires some ingenuity asdescribed in the literature where the number of water molecules N in the pocket is approximated by a continuous function.39−41 Based on an analysis of the pair-correlation function of water moleculeswith respect to the position of the center-of-mass of the pocket,we count all water molecules within an effective cutoff distance r0 = 0.5 nm of the center of mass of the pocketas “pocket water molecules”. We then take the coarse-grainedwater occupancy number N in the pocket to bewhere r is the distance ofthe oxygen atom of each water molecule from center of mass position, rcom, of the binding pocket,that is r = /rW – rcom/, andthe summation runs over all water molecules in the simulation box.As shown in Figure 2, this coarse-grained representationof the water occupation number reproduces the time profile of ‘atomistic‘water number reasonably well and makes it possible to apply restraintsto bias the pocket-water occupancy in an umbrella sampling simulationof the water occupancy number. With this definition, the pocket wateroccupancy is a continuous variable that adopts noninteger values,and its corresponding probability distribution P(N) (and free energy G(N) = −kBT ln P(N)) becomes a continuous function.

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