From Dipeptide Systems to Polypeptides: Evolution of Mutual Information.

Understanding the electronic structure of amino acids is crucial to understanding protein stability, folding mechanisms, and molecular interactions. In this study, we introduce fragment-wise mutual information (FMI) as a quantum information-based tool to quantify interatomic correlations in peptides. By extending mutual information (MI) analysis to amino acid fragments, FMI provides a detailed map of electronic interactions beyond classical descriptors, such as van der Waals forces. We first validated FMI on 400 dipeptides, demonstrating a correlation with the atomization and bonding energies. Expanding this approach to the 10-mer Neh2 peptide, we analyze molecular dynamics (MD) simulations and reveal how interatomic correlations evolve during folding. Our results show that FMI distinguishes stabilizing interactions such as salt bridges and variable hydrogen-bond strengths, providing deeper insight into peptide stability. These findings suggest that FMI could enhance molecular modeling and force-field development by incorporating quantum electronic effects into biomolecular analysis.