Dielectric screening effect of electronic polarization and intramolecular hydrogen bonding

Recent site-resolved hydrogen exchange measurements have uncovered significant discrepancies between simulations and experimental data during protein folding, including the excessive intramolecular hydrogen bonds in simulations. This finding indicates a possibility that intramolecular charge–charge interactions have not included sufficient dielectric screening effect of the electronic polarization. Scaling down peptide atomic charges according to the optical dielectric constant is tested in this study. As a result, the number of intramolecular hydrogen bonds is lower than using unscaled atomic charges while reaching the same levels of helical contents or β-hairpin backbone hydrogen bonds, because van der Waals interactions contribute substantially to peptide folding in water. Reducing intramolecular charge–charge interactions and hydrogen bonding increases conformational search efficiency. In particular, it reduces the equilibrium helical content in simulations using AMBER force field and the energy barrier in folding simulations using CHARMM force field.