pH-dependent structural dynamics of the neuropeptide Y in aqueous solution

ABSTRACT. The neuropeptide Y regulates key molecular processes in the brain. Its interaction with the cell membrane, where it binds to specialized receptors with key physiological roles, likely depends on the pH. The structural ensembles of the porcine and human peptides, solved by Nuclear Magnetic Resonance (NMR) acid pH in aqueous solution, indicate an α -helical core with unstructured termini. However, the protonation states of the carboxylic and histidine residues of the peptide, and the interplay between protonation states and peptide conformational dynamics, have not been explored. Here we perform constant pH simulations and graph-based analyses to investigate dynamics and H-bond patterns of the neuropeptide Y in the pH range from 3.0 to 7.0. We find that an α -helical core, as observed in the NMR experiments, is presented at all pH values, though its length can vary by 2-3 residues depending on the pH. The pK a of Asp16, part of the α -helix, and of Asp11 may shift by more than on pH unit. Based on these findings, we suggest that performing constant pH simulations may be required to describe accurately the interactions of the peptide with its cellular partners at the pH values of interest.