Multiscale Reactive Molecular Dynamics for Absolute pKa Predictions and Amino Acid Deprotonation

Accurately calculating a weak acid's pK(a) from simulations remains a challenging task. We report a multiscale theoretical approach to calculate the free energy profile for acid ionization, resulting in accurate absolute pK(a) values in addition to insights into the underlying mechanism. Importantly, our approach minimizes empiricism by mapping electronic structure data (QM/MM forces) into a reactive molecular dynamics model capable of extensive sampling. Consequently, the bulk property of interest (the absolute pK(a)) is the natural consequence of the model, not a parameter used to fit it. This approach is applied to create reactive models of aspartic and glutamic acids. We show that these models predict the correct pKa values and provide ample statistics to probe the molecular mechanism of dissociation. This analysis shows changes in the solvation structure and Zundel-dominated transitions between the protonated acid, contact ion pair, and bulk solvated excess proton.