RT Journal Article
SR Electronic
T1 Binding Thermodynamics and Kinetics Calculations Using Chemical Host and Guest: A Comprehensive Picture of Molecular Recognition
JF bioRxiv
FD Cold Spring Harbor Laboratory
SP 155275
DO 10.1101/155275
A1 Zhiye Tang
A1 Chia-en A. Chang
YR 2017
UL http://biorxiv.org/content/early/2017/08/24/155275.abstract
AB 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 β-cyclodextrin (β-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, ΔH, ΔS, and ΔG using GAFF-CD and q4MD-CD force fields for β-CD could be compared with experimental data directly and agreed reasonably with experiment findings. Both force fields resulted in similar computed ΔG from independently computed kinetics rates, ΔG=-RTln(kon · C° / k off), and thermodynamics properties, ΔG=ΔH – TΔS. 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 β-CD as well. Water molecules play a crucial role in guest binding to β-CD. However, collective water/β-CD motions could contribute to different computed kon and ΔH values by different force fields, mainly because the parameters of β-CD provide different motions of β-CD, hydrogen-bond networks of water molecules in the cavity of free β-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.