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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

Free energy profile (PMF) of ligand-approach (red curve,left scale)and profile of number of pocket-water (black curve, right scale) asa function of the distance d between the pocket andligand centers of mass. Inset: The free energy profile is zoomed inbetween d of 0.75 and 0.95 nm to show the free energybarrier due to dewetting.
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fig3: Free energy profile (PMF) of ligand-approach (red curve,left scale)and profile of number of pocket-water (black curve, right scale) asa function of the distance d between the pocket andligand centers of mass. Inset: The free energy profile is zoomed inbetween d of 0.75 and 0.95 nm to show the free energybarrier due to dewetting.

Mentions: The free energy profile,or PMF, of the binding complex as a functionof the distance, d, is shown in Figure 3 (left-hand scale). The distance d is a simplereaction coordinate containing no orientational bias that providessome insight into the binding process yet, as is well-known, the choiceof reaction coordinate is critical and the results will be sensitiveto its choice. As we shall see, it will be necessary to augment thischoice at the very least with the solvent occupation number. Nevertheless,as shown below, the choice of d generates some interestingobservations. We find for example that as the ligand approaches thepocket from d = 1.5 nm to d = 0.95nm, the free energy profile remains almost flat. However, as shown in the inset of Figure 3, as the ligand passes from d = 0.95 nm to d = 0.75 nm, it has to surmount a free energy barrier ofmore than 4.0 kcal/mol at an intermediate ligand-pocket distance.We also observe a weak shoulder at d = 0.65 nm, andwe find this is mainly steric in origin resulting from the pocket-ligandinteraction. At closer separations d < 0.75 nm,a steep decrease in free energy is observed before the ligand settlesinto a deep global free-energy minimum at d = 0.4nm. At short distances, d < 0.4 nm, the free energyincreases, mainly due to steric repulsions between pocket-wall andligand. We have checked the reliability of the PMF landscape and thecorresponding pocket-water profile, by repeating the same umbrellasampling simulation for a different set of initial configurations.As depicted in Figures S1 and S2 of the SupportingInformation, the two different sets of umbrella sampling simulationresults are in reasonable mutual agreement. The approximate agreementof two simulations does not of course provide a rigorous estimationof the error, but it does suggest that there are not any immediatelyobvious major sampling problems. We have also provided the convergenceplot of number of pocket-water profile along with the measure of standarddeviation from average profile in Figure S6 of the Supporting Information.


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

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

Free energy profile (PMF) of ligand-approach (red curve,left scale)and profile of number of pocket-water (black curve, right scale) asa function of the distance d between the pocket andligand centers of mass. Inset: The free energy profile is zoomed inbetween d of 0.75 and 0.95 nm to show the free energybarrier due to dewetting.
© Copyright Policy
Related In: Results  -  Collection

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

fig3: Free energy profile (PMF) of ligand-approach (red curve,left scale)and profile of number of pocket-water (black curve, right scale) asa function of the distance d between the pocket andligand centers of mass. Inset: The free energy profile is zoomed inbetween d of 0.75 and 0.95 nm to show the free energybarrier due to dewetting.
Mentions: The free energy profile,or PMF, of the binding complex as a functionof the distance, d, is shown in Figure 3 (left-hand scale). The distance d is a simplereaction coordinate containing no orientational bias that providessome insight into the binding process yet, as is well-known, the choiceof reaction coordinate is critical and the results will be sensitiveto its choice. As we shall see, it will be necessary to augment thischoice at the very least with the solvent occupation number. Nevertheless,as shown below, the choice of d generates some interestingobservations. We find for example that as the ligand approaches thepocket from d = 1.5 nm to d = 0.95nm, the free energy profile remains almost flat. However, as shown in the inset of Figure 3, as the ligand passes from d = 0.95 nm to d = 0.75 nm, it has to surmount a free energy barrier ofmore than 4.0 kcal/mol at an intermediate ligand-pocket distance.We also observe a weak shoulder at d = 0.65 nm, andwe find this is mainly steric in origin resulting from the pocket-ligandinteraction. At closer separations d < 0.75 nm,a steep decrease in free energy is observed before the ligand settlesinto a deep global free-energy minimum at d = 0.4nm. At short distances, d < 0.4 nm, the free energyincreases, mainly due to steric repulsions between pocket-wall andligand. We have checked the reliability of the PMF landscape and thecorresponding pocket-water profile, by repeating the same umbrellasampling simulation for a different set of initial configurations.As depicted in Figures S1 and S2 of the SupportingInformation, the two different sets of umbrella sampling simulationresults are in reasonable mutual agreement. The approximate agreementof two simulations does not of course provide a rigorous estimationof the error, but it does suggest that there are not any immediatelyobvious major sampling problems. We have also provided the convergenceplot of number of pocket-water profile along with the measure of standarddeviation from average profile in Figure S6 of the Supporting Information.

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