Efficient Sampling and Characterization of Free Energy Landscapes of Ion-Peptide Systems

Proteins that influence nucleation, growth, or polymorph selection during biomineralization processes are often rich in glutamic- or aspartic acid. Here, the interactions between carboxylate side chains and ions lead to an interplay of peptide conformations and ion structuring in solution. Molecular dynamics simulations are an ideal tool to mechanistically investigate these processes. Unfortunately, the formation of strong ion-peptide contacts and ion bridges drastically impedes structural reorganization of ionic bonds and conformational transitions of the polymers. Thus, to obtain a complete thermodynamical picture of such systems, enhanced sampling techniques become necessary as well as the methods to characterize the conformational states of these partially disordered polymer-ion systems. Here, we propose a new set of Hamiltonian replica exchange (HRE) parameters for efficient simulations of peptide-ion systems, with an aspartic acid trimer in the presence of Ca²⁺ and Cl^- ions as a test system. We introduce dimensionality reduction and clustering strategies to characterize the states of such a multicomponent system and to analyze the outcome of the proposed HRE with different reweighting methods.