Conformational Ensembles from Experimental Data and Computer Simulations

Conformational Ensembles from Experimental Data and Computer Simulations

Poster Abstracts

103-POS Board 23 Linking Kinetics and Thermodynamics of Biomolecular Conformational Transformations and Ligand Binding

Yong Wang , Joao M. Martins, Kresten Lindorff-Larsen. University of Copenhagen, Copenhangen, Denmark.

The accurate calculation of thermodynamics and kinetics in biomolecular conformational transformations and ligand binding is a problem of critical importance but tremendous challenges in computational biology and computer-aided drug design. Instead of pursuing a one-shot solution, for example by long equilibrium molecular dynamics simulations, one usually adopts a divide-and-conquer strategy by which the binding free energy (ΔG) is calculated by enhanced sampling methods or alchemical methods, while the binding rate (kon) is obtained from binding events with high ligand concentrations. From known ΔG and kon, the unbinding rate koff can be estimated analytically. In this work, we seek the possibility to address the thermodynamics- kinetics problem through a novel route by which the kinetics (both kon and koff) is calculated first and subsequently is used to estimate ΔG. By taking a simple two-state and a four-state model system as examples, we show that such `kinetic' ΔG can reach promising consistence with thermodynamic ΔG obtained from free energy profiles with a mean absolute error of 0.6 kcal/mol. The feasibility is further supported by the application on the binding of a cavity mutant of T4 lysozyme with benzene in which ΔGbinding values from kinetics, free energy perturbation method and experiments are all in good agreement. The approach both sheds light on the accuracy of methods for calculating kinetics and further provides a generally useful test for the internal consistency of kinetics and thermodynamics. We also expect it to be useful for estimating thermodynamic properties in cases where equilibrium sampling or alchemical methods are difficult to apply, for example in the case of conformational exchange.

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