Accurate and cost-effective NMR chemical shift predictions for proteins using a molecules-in-molecules fragmentation-based method

We have developed an efficient protocol using our two-layer Molecules-in-Molecules (MIM2) fragmentation-based quantum chemical method for the prediction of NMR chemical shifts of large biomolecules. To investigate the performance of our fragmentation approach and demonstrate its applicability, MIM-NMR calculations are first calibrated on a test set of six proteins. The MIM2-NMR method yields a mean absolute deviation (MAD) from unfragmented full molecule calculations of 0.01 ppm for H-1 and 0.06 ppm for C-13 chemical shifts. Thus, the errors from fragmentation are only about 3% of our target accuracy of similar to 0.3 ppm for H-1 and 2-3 ppm for C-13 chemical shifts. To compare with experimental chemical shifts, a standard protocol is first derived using two smaller proteins ; 2LHY (176 atoms) and ; 2LI1 (146 atoms) for obtaining an appropriate protein structure for NMR chemical shift calculations. The effect of the solvent environment on the calculated NMR chemical shifts is incorporated through implicit, explicit, or explicit-implicit solvation models. The expensive first solvation shell calculations are replaced by a micro-solvation model in which only the immediate interaction between the protein and the explicit solvation environment is considered. A single explicit water molecule for each amine and amide proton is found to be sufficient to yield accurate results for H-1 chemical shifts. The H-1 and C-13 NMR chemical shifts calculated using our protocol give excellent agreement with experiments for two larger proteins, ; 2MC5 (the helical part with 265 atoms) and ; 3UMK (33 residue slice with 547 atoms). Overall, our target accuracy of similar to 0.3 ppm for H-1 and similar to 2-3 ppm for C-13 has been achieved for the larger proteins. The proposed MIM-NMR method is accurate and computationally cost-effective and should be applicable to study a wide range of large proteins.