NMR Chemical Shifts Calculation Of Molecular Crystal Based On Fragmentation Quantum Mechanical Method

Nuclear magnetic resonance（NMR）plays an important role in the determination and prediction of the structure of molecules,while molecular crystals occupy an important position in scientific fields such as materials chemistry,medicinal chemistry,and biochemistry.Therefore,the NMR-related research on molecular crystals is of extraordinary significance.The NMR chemical shifts of ¹³C and ¹H in molecular crystals was calculated by automated fragmentation quantum mechanical/molecular mechanics（AF-QM/MM）approach.Firstly,two benchmark sets of molecular crystals were selected to calculate the NMR chemical shifts.Systematic investigation was conducted to assess the convergence of AF-QM/MM calculations,and the impact of various density functionals with different basis sets on the NMR chemical shift prediction.The results show that the calculated NMR chemical shifts are close to converge when the distance threshold for the QM region is larger than 3.5（?）.For the calculation of ¹³C NMR chemical shifts,the m PW1PW91 functional is the best density functional among the functionals chosen in this study（namely,B3LYP,B3PW91,M06-2X,M06-L,m PW1PW91,OB98,OPBE）,while the OB98 functional is more suitable for ¹H NMR chemical shift prediction of molecular crystals.To be consistent with the experimental¹³C and ¹H chemical shifts,at least a triple-ζbasis set should be employed with the B3LYP functional.The employment of diffuse basis functions will further improve the accuracy for ¹³C chemical shift calculations,but not for ¹H chemical shift prediction.We further proposed a fragmentation scheme of dividing the central molecule into smaller fragments.By comparing with the results of the fragmentation scheme using the entire central molecule as the core region,the AF-QM/MM calculations with the fragmented central molecule can not only achieve accurate results,but also reduce the computational cost.Therefore,the AF-QM/MM approach is capable of predicting the ¹³C and ¹H NMR chemical shifts for molecular crystals accurately and effectively,and could be utilized for dealing with more complex periodic systems such as macromolecular polymers and biomacromolecules.Secondly,the B3LYP functional was selected to calculate the NMR of the HIV integrase inhibitor Cabotegravir（GSK744）molecular crystals for the treatment of AIDS,and the above-mentioned basis sets determination results were verified.This part of the research may have an effect on the determination and prediction of the molecular crystal structure of Cabotegravir.