Conformational Ensembles from Experimental Data and Computer Simulations

Conformational Ensembles from Experimental Data

and Computer Simulations

Poster Abstracts

140

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.