Ab Initio Molecular Dynamics Simulations of Amino Acids in Aqueous Solutions: Estimating pKa Values from Metadynamics...

Changes in the protonation and deprotonation of amino acid residues in proteins play a key role in many biological processes and pathways. Here, we report calculations of the free-energy profile for the protonation-deprotonation reaction of the 20 canonical α amino acids in aqueous solutions using ab initio Car-Parrinello molecular dynamics simulations coupled with metadynamics sampling. We show here that the calculated change in free energy of the dissociation reaction provides estimates of the multiple pKa values of the amino acids that are in good agreement with experiment. We use the bond-length-dependent number of the protons coordinated to the hydroxyl oxygen of the carboxylic and the amine groups as the collective variables to explore the free-energy profiles of the Bronsted acid-base chemistry of amino acids in aqueous solutions. We ensure that the amino acid undergoing dissociation is solvated by at least three hydrations shells with all water molecules included in the simulations. The method works equally well for amino acids with neutral, acidic and basic side chains and provides estimates of the multiple pKa values with a mean relative error, with respect to experimental results, of 0.2 pKa units.