Harnessing the Peripheral Surface Information Entropy from Globular Protein-Peptide Complexes

TL;DR

This paper introduces PSI entropy, a new measure of surface variability in protein-peptide complexes, revealing that favorable binders tend to have low-entropy surface states, which are consistent across computational and experimental data.

Contribution

The study presents PSI entropy as a novel thermoinformatic descriptor that captures binding constraints through surface state signatures, validated across multiple systems and experimental structures.

Findings

Favorable binders show low-entropy N-states in surface configurations.

Dominant NIS modes are consistent across different computational methods.

Experimental WW domain structures confirm the presence of NIS modes.

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, a quantitative measure of the statistical variability in apolar and charged non-interacting surface (NIS) proportions across conformational ensembles. 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. An experimental meta-ensemble of WW domains from 36 high-resolution structures confirmed the presence of dominant NIS modes independent of in silico methodology, suggesting an evolutionary selection pressure toward specific NIS fingerprints. These findings establish PSI entropy as a thermoinformatic descriptor that encodes favorable binding constraints into unique statistical signatures of the NIS.