Including Crystallographic Symmetry in Quantum-based Refinement: Q|R#2

Abstract

Three-dimensional structure models refined using low-resolution data from crystallographic or electron cryo-microscopy experiments can benefit from high quality restraints derived from quantum chemical methods. However, non-periodic atom-centered quantum chemistry codes do not inherently account for nearest neighbor interactions of crystallographic symmetry related copies in a satisfactory way. Herein, we have included these nearest neighbor effects in our model by expanding to a super-cell, and then truncating the super-cell to only include residues from neighboring cells that are interacting with the asymmetric unit. In this way our fragmentation approach can adequately and efficiently include the nearest neighbor effects. We have shown previously that a moderately sized X-ray structure can be treated with quantum methods if a fragmentation approach was applied. In this study, we partition a target protein (4gif) into a number of large fragments. The use of large fragments (typically hundreds of atoms) is tractable when a GPU based package such as TeraChem is employed or cheaper (semi-empirical) methods are used. We run the QM calculations at the HF-D3/6-31G level. We compare and contrast the models refined using a recently developed semi-empirical method (GFN2-xTB). To validate the refinement procedure for a non-P1 structure, we use a standard set of crystallographic metrics. We show the robustness of our implementation by refining 13 additional protein models across multiple space-groups and present the summary of the refinement metrics.\n\nSynopsisC-terminal coiled-coil domain of transient receptor potential channel TRPP3 in the P321 space group (PDB code: 4gif) is re-refined with restraints from quantum chemistry using Hartree-Fock theory.