Theoretical evidence for temperature-induced proton mobility in isolated lysine-rich polyalanines

A multistate molecular mechanics method is introduced to model the possible competition between various protonation sites in gas-phase biomolecules with excess protons. The method relies on the Amber force field for each site and is calibrated against density-functional theory benchmark calculations at the 6-31+G(d,p) level. In its adiabatic version, where it has similarities with constant-pH algorithms, the model predicts that the small protonated Ala(4)-Lys peptide, unprotected at the N-terminus, changes protonation site above 400 K. In the larger [Ala(9)-Lys+H ](+) peptide, the proton remains at the lysine amine group in a favored charge/electric dipole conformation. In the three-state Ala(4)-Lys-Ala(4)-Lys peptide, the excess proton is found to be partially delocalized on the amine group of the first lysine and on the N-terminus. The statistical properties of the protonated peptides are found to significantly depend on the localized character of the proton. Finally, the model is extended by considering possible couplings between the protonation sites, in an empirical valence-bond version. Strong couplings can stabilize the peptides into unexpected proton-bound conformations over broad ranges of temperature.