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

Tyler Grear; Donald J. Jacobs

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arXiv · 2602.00498

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

Tyler Grear·Donald J. Jacobs

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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.

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Tyler Grear, Donald J. Jacobs. 2026-01-31. Harnessing the Peripheral Surface Information Entropy from Globular Protein-Peptide Complexes. https://arxiv.org/abs/2602.00498

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