Protein structure validation and refinement using amide proton chemical shifts derived from quantum mechanics

TL;DR

ProCS is a quantum mechanics-based method for rapidly predicting amide proton chemical shifts, enabling high-accuracy protein structure validation and refinement, especially of hydrogen bonding networks, with broad potential applications.

Contribution

This work introduces ProCS, a novel QM-parameterized tool integrated with PHAISTOS for accurate protein structure refinement using chemical shift data.

Findings

ProCS achieves RMSD of 0.25 ppm in QM predictions.

Refinements improve agreement with experimental chemical shifts.

Structural sensitivity of chemical shifts is crucial for accurate refinement.

Abstract

We present the ProCS method for the rapid and accurate prediction of protein backbone amide proton chemical shifts - sensitive probes of the geometry of key hydrogen bonds that determine protein structure. ProCS is parameterized against quantum mechanical (QM) calculations and reproduces high level QM results obtained for a small protein with an RMSD of 0.25 ppm (r = 0.94). ProCS is interfaced with the PHAISTOS protein simulation program and is used to infer statistical protein ensembles that reflect experimentally measured amide proton chemical shift values. Such chemical shift-based structural refinements, starting from high-resolution X-ray structures of Protein G, ubiquitin, and SMN Tudor Domain, result in average chemical shifts, hydrogen bond geometries, and trans-hydrogen bond (h3JNC') spin-spin coupling constants that are in excellent agreement with experiment. We show that the structural sensitivity of the QM-based amide proton chemical shift predictions is needed to refine protein structures to this agreement. The ProCS method thus offers a powerful new tool for refining the structures of hydrogen bonding networks to high accuracy with many potential applications such as protein flexibility in ligand binding.