Electron cryo-microscopy (cryo-EM) is rapidly becoming a major competitor to X-ray crystallography, especially for large structures that are difficult or impossible to crystallize. While recent spectacular technological improvements have led to significantly higher resolution three-dimensional reconstructions, the average quality of cryo-EM maps is still at the low-resolution end of the range compared with crystallography. A long-standing challenge for atomic model refinement has been the production of stereochemically meaningful models for this resolution regime. Here, it is demonstrated that including accurate model geometry restraints derived from ab initio quantum-chemical calculations (HF-D3/6-31G) can improve the refinement of an example structure (chain A of PDB entry 3j63). The robustness of the procedure is tested for additional structures with up to 7000 atoms (PDB entry 3a5x and chain C of PDB entry 5fn5) using the less expensive semi-empirical (GFN1-xTB) model. The necessary algorithms enabling real-space quantum refinement have been implemented in the latest version of qr.refine and are described here.

Institute of Biophysics of the Czech Academy of Sciences Brno Czech Republic

International Center for Quantum and Molecular Structures Shanghai University Shanghai 200444 People's Republic of China

Molecular Biosciences and Integrated Bioimaging Lawrence Berkeley National Laboratory Berkeley CA 94720 USA

Pending AI Pty Ltd iAccelerat Innovation Campus North Wollongong NSW 2500 Australia

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