Ab initio quantum mechanical calculation of protein in solution is carried out to generate polarized protein-specific charge(s) (PPC) for molecular dynamics (MD) stimulation of protein. The quantum calculation of protein is made possible by developing a fragment-based quantum chemistry approach in combination with the implicit continuum solvent model. The computed electron density of protein is utilized to derive PPCs that represent the polarized electrostatic state of protein near the native structure. These PPCs are atom-centered like those in the standard force fields and are thus computationally attractive for molecular dynamics simulation of protein. Extensive MD simulations have been carried out to investigate the effect of electronic polarization on the structure and dynamics of thioredoxin. Our study shows that the dynamics of thioredoxin is stabilized by electronic polarization through explicit comparison between MD results using PPC and AMBER charges. In particular, MD free-energy calculation using PPCs accurately reproduced the experimental value of pK(a) shift for ionizable residue Asp(26) buried inside thioredoxin, whereas previous calculations using standard force fields overestimated pK(a) shift by twice as much. Accurate prediction of pK(a) shifts by rigorous MD free energy simulation for ionizable residues buried inside protein has been a significant challenge in computational biology for decades. This study presented strong evidence that electronic polarization of protein plays an important role in protein dynamics.

The prevalence of IBD has increased in Wuhan City, central China, but is not as high as in Western countries. The disease in Wuhan City has often been associated with young adult professional males with a high level of education. The clinical presentation of UC was often mild and had few extra intestinal manifestations.

Free energy profile (FE Profile) is an essential quantity for the estimation of reaction rate and the validation of reaction mechanism. For chemical reactions in condensed phase or enzymatic reactions, the computation of FE profile at the ab initio (ai) quantum mechanical/molecular mechanics (QM/MM) level is still far too expensive. Although semiempirical (SE) method can be hundreds or thousands of times faster than the ai methods, the accuracy of SE methods is often unsatisfactory due to the approximations that have been adopted in these methods. In this work, we propose a new method termed MBAR +wTP in which the ai QM/MM free energy profile is computed by a weighted thermodynamic perturbation (TP) correction to the SE profile generated by the multistate Bennett acceptance ratio (MBAR) analysis of the trajectories from umbrella samplings (US). The weight factors used in the TP calculations are a byproduct of the MBAR analysis in the postprocessing of the US trajectories, which are often discarded after the free energy calculations. The raw ai QM/MM free energy profile is then smoothed using Gaussian process regression in which the noise of each datum is set to be inversely proportional to the exponential of the reweighting entropy. The results show that this approach can enhance the efficiency of ai FE profile calculations by several orders of magnitude with only a slight loss of accuracy. This method can significantly enhance the applicability of ai QM/MM methods in the studies of chemical reactions in condensed phase and enzymatic reactions.