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

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-time-scale molecular dynamics (MD) simulations, postanalysis and numerical calculations. We computed association and dissociation rate constants, enthalpy, and solvent and solute entropy of binding. All the computed values of k(on), k(off), 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. In addition, our study further interprets experiments. Both force fields resulted in similar computed Delta G from independently computed kinetics rates, Delta G = -RT1n(k(on)center dot C-0/k(off)), and thermodynamics properties, Delta G = -Delta H - T Delta S. The water entropy calculations show that the entropy gain of desolvating water molecules are a major driving force, and both force fields have the same strength of nonpolar 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 icon and OH 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 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 driving force of binding. The study deepens our understanding of ligand-receptor recognition and suggests strategies for force field parametrization for accurately modeling molecular systems.