Direct absolute pK_a predictions and proton transfer mechanisms of small molecules in aqueous solution by QM/MM-MD

The pK_a values of HF, HCOOH, CH₃COOH, CH ₃CH₂COOH, H₂CO₃, HOCl, NH ₄⁺, CH₃NH₃⁺, H ₂O₂, and CH₃CH₂OH in aqueous solution were predicted by QM/MM-MD in combination with umbrella samplings adopting the flexible asymmetric coordinate (FAC). This unique combination yielded remarkably accurate values with the maximum and root-mean-square errors of 0.45 and 0.22 in pK_a units, respectively, without any numerical or experimental adjustments. The stability of the initially formed Coulomb pair rather than the proton transfer stage turned out to be the rate-determining step, implying that the stabilizations of the created ions require a large free energy increase. A remarkable correlation between DWR (degree of water rearrangements) and pK_a was observed. As such, the large pK _a of ethanol can be, in part, attributed to the large water rearrangement, strongly suggesting that proper samplings of water dynamics at dissociated regions are critical for accurate predictions of pK_a. Current results exhibit a promising protocol for direct and accurate predictions of pK_a. The significant variations in the gas phase deprotonation energies with level of theory appear to be mostly canceled by the similar changes in the averaged solute-solvent interactions, yielding accurate results.