Ab Initio Molecular Dynamics Simulations of Amino
Acids in Aqueous Solutions: Estimating p<i>K</i><sub>a</sub> Values from Metadynamics Sampling
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Abstract
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 p<i>K</i><sub>a</sub> 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 p<i>K</i><sub>a</sub> values with a mean
relative error, with respect to experimental results, of 0.2 p<i>K</i><sub>a</sub> units