Binding Thermodynamics and Kinetics Calculations Using Chemical Host and Guest: A Comprehensive Picture of Molecular Recognition

Abstract

Understanding the fine balance between changes of entropy and enthalpy and the competition between a guest and water molecules in molecular binding is crucial in fundamental studies and practical applications. Experiments provide measurements. However, illustrating the binding/unbinding processes gives a complete picture of molecular recognition not directly available from experiments, and computational methods bridge the gaps. Here, we investigated guest association/dissociation with {beta}-cyclodextrin ({beta}-CD) by using microsecond-timescale molecular dynamics (MD) simulations, post-analysis and numerical calculations. We computed association and dissociation rate constants, enthalpy, and solvent and solute entropy of binding. All the computed values of kon, koff, {Delta}H, {Delta}S, and {Delta}G using GAFF-CD and q4MD-CD force fields for {beta}-CD could be compared with experimental data directly and agreed reasonably with experiment findings. Both force fields resulted in similar computed {Delta}G from independently computed kinetics rates, {Delta}G=-RTln(kon {middle dot} C{degrees} / k off), and thermodynamics properties, {Delta}G={Delta}H - T{Delta}S. The water entropy calculations show that entropy gain of desolvating water molecules are a major driving force, and both force fields have the same strength of non-polar attractions between solutes and {beta}-CD as well. Water molecules play a crucial role in guest binding to {beta}-CD. However, collective water/{beta}-CD motions could contribute to different computed kon and {Delta}H values by different force fields, mainly because the parameters of {beta}-CD provide different motions of {beta}-CD, hydrogen-bond networks of water molecules in the cavity of free {beta}-CD and the strength of desolvation penalty. As a result, q4MD-CD suggests that guest binding is mostly driven by enthalpy, while GAFF-CD shows that gaining entropy is the major driven force of binding. The study further interprets experiments, deepens our understanding of ligand binding, and suggests strategies for force field parameterization.