Configurational Entropy in Protein–Peptide Binding:: Computational Study of Tsg101 Ubiquitin E2 Variant Domain with an HIV-Derived PTAP Nonapeptide

Configurational entropy is thought to influence biomolecular processes, but there are still many open questions about this quantity, including its magnitude, its relationship to molecular structure, and the importance of correlation. The mutual information expansion (MIE) provides a novel and systematic approach to extracting configurational entropy changes due to correlated motions from molecular simulations. We present the first application of the MIE method to protein–ligand binding using multiple molecular dynamics simulations to study the association of the ubiquitin E2 variant domain of the protein Tsg101 and an HIV-derived nonapeptide. This investigation utilizes the second-order MIE approximation, which accounts for correlations between all pairs of degrees of freedom. The computed change in configurational entropy is large and has a major contribution from changes in pairwise correlation. The results also reveal intricate structure–entropy relationships. Thus, the present analysis suggests that in order for a model of binding to be accurate, it must include a careful accounting of configurational entropy changes.