Investigation of the Interactions and pH-Dependent Structural Changes in Helical Peptides by Molecular Dynamics Simulations

Electrostatic interactions between charged amino acid side chains play an important role for the stability of α-helices. The strength of these interactions depends on the protonation state of the residues, which is determined by the pH of the environment. Force fields used for molecular dynamics (MD) simulations of such systems should therefore accurately model charged interactions and their dependence on the protonation state. We performed MD simulations for two distinct protonation states on a set of helical peptides known to exhibit various degrees of pH-dependence in experiments and compared two recommended combinations of AMBER protein force field and water model: ff14SB + TIP3P and ff19SB + OPC. While both combinations model similar side chain interactions for the helical states of the peptides, they showed some differences in the overall helical content and the stability of the hydrogen bonds. Nevertheless, both combinations were capable of detecting protonation-dependent structural changes in the peptides. This could be useful for identifying pH-sensitive sites in helical peptides or for designing pH-dependent switches.