We evaluate the contribution of water to the change of the entropy of proteins when they bind. The entropy of the free and complex forms of the proteins is computed from molecular dynamics simulations in explicit solvent using a theory previously applied on liquids and isolated flexible molecules from. The total entropy is decoupled into a “vibrational” term and a “topographical” term which collectively describe the accessibility of the states sampled by the solvated system. The vibrational term, which quantifies the density of vibrational energy states in a harmonic well, is derived from the diagonalization of a hierarchy-scalable force-torque covariance matrix which is constituted using the forces acting on atoms (or a group of atoms) during the simulation. The topographical term, which describes the population of the energy wells, is derived from computing the correlated occupancy of these wells. As the total entropy change of proteins upon binding is determined, the changes incurred individually by these terms is also inspected. Through our analyses on 40 protein complexes, we show that exposure to the water influences both of the terms differently. Quite contrary to the common intuition, increased exposure of a protein’s residues to water shows a decrease in its vibrational density of states but an increase in the population of energy wells it can sample. Our findings complement the observations made by inelastic neutron scattering experiments, which indicate increased “softening” upon complexation. On account of our analyses, we present an atomic level examination of the phenomena and its counterintuitive components. The entropic changes are also assessed in the backdrop of enthalpy changes, computed using MM/PBSA, that occur upon binding in order to understand the degree to which water can influence the total Gibbs free energy.<br/>

Effect of water on the entropy of protein-protein binding

2019 Fall National Meeting

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