Automated Fragmentation QM/MM Calculation of Amide Proton Chemical Shifts in Proteins with Explicit Solvent Model.

We have performed a density functional theory (DFT) calculation of the amide proton NMR chemical shift in proteins using a recently developed automated fragmentation quantum mechanics/molecular mechanics (AF-QM/MM) approach. Systematic investigation was carried out to examine the influence of explicit solvent molecules, cooperative hydrogen bonding effects, density functionals, size of the basis sets, and the local geometry of proteins on calculated chemical shifts. Our result demonstrates that the predicted amide proton ((1)HN) NMR chemical shift in explicit solvent shows remarkable improvement over that calculated with the implicit solvation model. The cooperative hydrogen bonding effect is also shown to improve the accuracy of (1)HN chemical shifts. Furthermore, we found that the OPBE exchange-correlation functional is the best density functional for the prediction of protein (1)HN chemical shifts among a selective set of DFT methods (namely, B3LYP, B3PW91, M062X, M06L, mPW1PW91, OB98, OPBE), and the locally dense basis set of 6-311++G**/4-31G* is shown to be sufficient for (1)HN chemical shift calculation. By taking ensemble averaging into account, (1)HN chemical shifts calculated by the AF-QM/MM approach can be used to validate the performance of various force fields. Our study underscores that the electronic polarization of protein is of critical importance to stabilizing hydrogen bonding, and the AF-QM/MM method is able to describe the local chemical environment in proteins more accurately than most widely used empirical models.