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

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 on
the protein. The new computational approach, 1H empirical
chemical shift perturbation (HECSP), has been developed to rapidly
calculate ligand binding-induced 1H 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/molecular
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 (1HA), 0.971 (1HN), and 0.945 (side chain 1H) with root-mean-square errors
of 0.151 (1HA), 0.199 (1HN), and 0.257 ppm (side
chain 1H), respectively. Using the HECSP model, we developed
a scoring function (NMRScore_P). We describe two applications of NMRScore_P
on two complex systems and demonstrate that the method 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 1H 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.