Quantifying the Peripheral Surface Information Entropy from Conformational Ensembles of Globular Protein-Peptide Complexes.

Abstract

Predicting favorable protein-peptide binding events remains a central challenge in biophysics, with continued uncertainty surrounding how nonlocal effects shape the global energy landscape. Here, we introduce peripheral surface information (PSI) entropy, SΨ, a quantitative measure of the statistical variability in apolar and charged non-interacting surface (NIS) proportions across conformational ensembles. Within the Gibbs free-energy relation ΔG = ΔH - TΔS, SΨ is proposed as a computationally tractable entropic proxy rather than a direct thermodynamic observable or stand-alone estimator of binding affinity. Using energy-directed molecular docking via HADDOCK3 and explicit-solvent molecular dynamics simulations, it is demonstrated that favorable binding partners exhibit emergent, low-entropy N-states (discrete macrostates in NIS state space) indicative of preferential apolar/charged surface configurations. Across dozens of peptides and multiple receptor systems (WW, PDZ, and MDM2 domains), dominant N-states persisted under varied docking parameters and initial conditions. A meta-ensemble of 657 complexes from 36 experiments over 15 years confirmed the presence of dominant NIS modes independent of in silico methodology, suggesting an evolutionary selection pressure toward specific NIS fingerprints. These findings establish SΨ as a thermoinformatic descriptor that encodes favorable binding constraints into unique statistical signatures of the NIS.