Unraveling pH-dependent peptide conformational transitions via integration of main mechanical forces and side-chain interactions

Abstract

The stability and flexibility of peptide structures are strongly influenced by environmental conditions, particularly pH. In this study, we investigate how changes in protonation states of pH-responsive residues modulate non-covalent interaction networks and drive conformational transitions. Using a β-hairpin peptide (PDB ID: 1K43) as a model system, we developed a tailored extension of the Main Mechanical Forces (MMFs) approach that explicitly accounts for side-chain protonation and its effects on non-covalent interaction patterns. Molecular dynamics (MD) simulations were performed to validate the MMFs-derived pH-related structural predictions and to provide complementary insights into pH-dependent conformational stability and flexibility of a peptide structure. The overall agreement between MMFs and MD results is an indication of the reliability of the proposed methodology. Overall, we present a refined MMFs-based methodological framework capable of predicting pH-dependent conformational transitions by systematically modelling changes in side-chain interaction patterns and non-covalent networks. This approach provides an effective calculation strategy for studying pH-responsive systems, which has potential to inform future simulation platforms focusing on peptide folding mechanisms.