Using Ligand-Induced Protein Chemical Shift Perturbations To Determine Protein Ligand Structures

作者：Yu Zhuoqin; Li Pengfei; Merz Kenneth M Jr^*

来源：Biochemistry, 2017, 56(18): 2349-2362.

DOI：10.1021/acs.biochem.7b00170

Protein chemical shift, perturbations (CSPs), upon ligand binding, can be used to refine the structure of a protein-ligand complex by comparing experimental CSPs with calculated CSPs for any given set of structural coordinates. Herein, we, describe a fast and accurate methodology that opens up new opportunities for improving the quality of protein ligand complexes using nuclear magnetic resonance (NMR)-based approaches by focusing on the effect of the ligand 911 the protein. The new computational approach, H-1 empirical chemical shift perturbation (HECSP), has been developed to rapidly calculate ligand binding-induced H-1 CSPs in a protein. Given the dearth of experimental information by which a model could be derived, we employed high-quality density functional theory (DFT) computations using the automated fragmentation quantum mechanics/naolecular mechanics approach to derive a database of ligand-induced CSPs on a series of protein ligand complexes. Overall, the empirical HECSP model yielded correlation coefficients between its predicted and DFT-computed values of 0.897 ((1)HA), 0.971 ((HN)-H-1), and 0.945 (side chain H-1) with root-mean-square errors of 0.151 ((1)HA), 0.199 ((HN)-H-1); and 0.257 ppm (side chain H-1), respectively. Using the HECSP model, we developed a scoring NMRScore_P). We describe two applications of NMRScore_P on two complex systems and demonstrate that the rnethod can distinguish native ligand poses from decoys and refine protein ligand complex structures. We provide further refined models for both complexes, which satisfy the observed H-1 CSPs in experiments. In conclusion, HECSP coupled with NMRScore_P provides an accurate and rapid platform by which protein ligand complexes can be refined using NMR-derived information.

• 出版日期2017-5-9