Water-Driven Cavity-Ligand Binding: Comparison of Thermodynamic Signatures from Coarse-Grained and Atomic-Level Simulations

The role of water (thermo)dynamics is crucial in molecular recognition and self-assembly. Here, we study a prototype cavity-ligand system as a model for hydrophobic noncovalent binding. Two alternative molecular dynamics simulation resolutions are employed and the resulting structural, dynamic, and thermodynamic properties compared: first, a coarse-grained (CG) resolution based on the previously reported and validated methane-like M solute and mW water models; second, an atomic-level (AL) resolution based on the popular OPLS united atom methane and the TIP4P water models. The CG model reproduces, as a function of the cavity ligand distance, (1) the water occupancy of the cavity, (2) the cavity ligand potential of mean force (free energy) and its temperature dependence, and (3) some of the major qualitative features of the thermodynamic signatures (free energy, enthalpy, and entropy) for cavity ligand association of the AL model. The limits of the CG and AI, models in this context are also discussed with comparison to experimental data. Our study suggests that CG simulation with models that include the translational contribution of water and anisotropic hydrogen-bond-like interactions could reproduce the thermodynamics of molecular recognition and water-driven assembly in complex macromolecular systems and nanoscale processes with convenient computational time savings.