The pK(a) values of HF, HCOOH, CH3COOH, CH3CH2COOH, H2CO3, HOCl, NH4+, CH3NH3+, H2O2, 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 plc 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 plc 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 plc. Current results exhibit a promising protocol for direct and accurate predictions of plc. 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.