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| Main Authors: | , |
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| Format: | Preprint |
| Published: |
2026
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| Subjects: | |
| Online Access: | https://arxiv.org/abs/2602.00498 |
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| _version_ | 1866911412959313920 |
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| author | Grear, Tyler Jacobs, Donald J. |
| author_facet | Grear, Tyler Jacobs, Donald J. |
| contents | 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. |
| format | Preprint |
| id |
arxiv_https___arxiv_org_abs_2602_00498 |
| institution | arXiv |
| publishDate | 2026 |
| record_format | arxiv |
| spellingShingle | Harnessing the Peripheral Surface Information Entropy from Globular Protein-Peptide Complexes Grear, Tyler Jacobs, Donald J. Biological Physics Information Theory 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. |
| title | Harnessing the Peripheral Surface Information Entropy from Globular Protein-Peptide Complexes |
| topic | Biological Physics Information Theory |
| url | https://arxiv.org/abs/2602.00498 |