Q|R: quantum-based refinement

Abstract

Quantum-based refinement utilizes chemical restraints derived from quantum-chemical methods instead of the standard parameterized library-based restraints used in refinement packages. The motivation is twofold: firstly, the restraints have the potential to be more accurate, and secondly, the restraints can be more easily applied to new molecules such as drugs or novel cofactors. Here, a new project called Q|R aimed at developing quantum-based refinement of biomacromolecules is under active development by researchers at Shanghai University together with PHENIX developers. The central focus of this long-term project is to develop software that is built on top of open-source components. A development version of Q|R was used to compare quantum-based refinements with standard refinement using a small model system.

Keywords: Q|R; X-ray diffraction; cctbx; cryo-EM; neutron diffraction; quantum refinement; structural biology.

Figure 1

A general model refinement workflow. See text for details.

Figure 2

Aldose reductase PDB structure (left) and extracted helix model (right), with hydrogen-bond distances shown in Å.

Figure 3

Perturbed models with r.m.s. deviations from the starting model of 0.3, 0.6, 0.9, 1.2 and 1.5 Å, overlaying ten models per perturbation. The average percentage of conserved hydrogen bonds at each perturbation level is shown in parentheses.

Figure 4

Average (a) R _work, (b) R _free and (c) R _free − R _work as a function of perturbation strength (Å) for semi-empirical (PM7), ab initio (HF/6-31G-D3), density functional [RI-BP86/SV(P)] and standard (cctbx) refinement. The average (ten trials per perturbation) starting R _work values are 0.15, 0.27, 0.35, 0.44 and 0.55, respectively, for each perturbation dose from 0.3 to 1.5 Å. Random noise (5%) was added to F _obs; therefore, R is expected to be around 0.05, which would correspond to the ideal structure.

Figure 5

The average percentage of recovered hydrogen bonds as a function of perturbation strength (Å) after refinement using either semi-empirical (PM7), ab initio (HF/6-31G-D3), density functional [RI-BP86/SV(P)] or standard (cctbx) refinement. The percentage of hydrogen bonds that remained in the perturbed models is also shown for comparison.