Automated fragmentation QM/MM calculation of NMR chemical shifts for protein-ligand complexes

In this study, the automated fragmentation quantum mechanics/molecular mechanics (AF-QM/MM) method was applied for NMR chemical shift calculations of protein-ligand complexes. In the AF-QM/MM approach, the protein binding pocket is automatically divided into capped fragments (within ~200 atoms) for density functional theory (DFT) calculations of NMR chemical shifts. Meanwhile, the solvent effect was also included using the Poission-Boltzmann (PB) model, which properly accounts for the electrostatic polarization effect from the solvent for protein-ligand complexes. The NMR chemical shifts of neocarzinostatin (NCS)-chromophore binding complex calculated by AF-QM/MM accurately reproduce the large-sized system results. The ¹H chemical shift perturbations (CSP) between apo-NCS and holo-NCS predicted by AF-QM/MM are also in excellent agreement with experimental results. Furthermore, the DFT calculated chemical shifts of the chromophore and residues in the NCS binding pocket can be utilized as molecular probes to identify the correct ligand binding conformation. By combining the CSP of the atoms in the binding pocket with the Glide scoring function, the new scoring function can accurately distinguish the native ligand pose from decoy structures. Therefore, the AF-QM/MM approach provides an accurate and efficient platform for protein-ligand binding structure prediction based on NMR derived information.