MS02-P04 Quantum refinement of X-ray and neutron protein crystal structures Octav Caldararu (Theoretical Chemistry, Lund University, Lund, Sweden) Lili Cao (Department of Theoretical Chemistry, Lund University, Lund, Sweden) Francesco Manzoni (Department of Biochemistry and Structural Biology, Lund University, Lund, Sweden) Esko Oksanen (Europen Spallation Source Consortium, Lund, Sweden) Derek Logan (Department of Biochemistry and Structural Biology, Lund University, Lund, Sweden) Ulf Ryde (Department of Theoretical Chemistry, Lund University, Lund, Sweden)email: octav.caldararu@teokem.lu.seCombining quantum mechanics and molecular mechanics (QM/MM) is one of the most important methods of studying the structure and function of proteins. This approach can also be applied in crystallographic refinement, as the geometry restraints used in refinement are in the form of an MM force-field. Thus, the MM potential for a small part of the molecule (for example, the active site of an enzyme) can be replaced by a QM potential, which can result in local improvement of protein crystal structures. We have developed such a method, quantum refinement, implemented in the ComQum-X program, which integrates a quantum chemical software with a crystallographic refinement software.
We present several recent applications of quantum refinement on both X-ray and neutron protein crystal structures. Firstly, we show how quantum refinement can help in determining the composition and geometry of the active site in metalloenzymes. For example, quantum refinement supports a model of particulate methane monooxygenase (pMMO) with only one copper atom in the active site instead of the two that the structure deposited in the PDB contains. (Cao et al., 2018) Secondly, we show a protonation study of the active site of nitrogenase. Quantum refinement predicts the correct protonation state of the homocitrate residue (Cao et al., 2017) and suggests that the FeMo-cluster is fully unprotonated in the resting-state crystal structure. Furthermore, we show some applications of the more recently developed ComQum-U (Manzoni et al., 2018), which combines quantum chemistry with joint X-ray and neutron refinement. This is especially useful in refining structures of enzymes that catalyze reactions that occur with proton transfer, in which case the neutron data may be unclear in the active site. To this end, we apply quantum refinement on the crystal structure of substrate-free lytic polysaccharide monooxygenase (LPMO) and on the crystal structure of triose phosphate isomerase (TIM) in complex with an inhibitor.
 
References:

Cao, L., Caldararu, O., Rosenzweig, A. C. & Ryde, U. (2018). Angew. Chemie - Int. Ed. 57,.

Cao, L., Caldararu, O. & Ryde, U. (2017). J. Phys. Chem. B. 121,.

Manzoni, F., Caldararu, O., Oksanen, E., Logan, D. T. & Ryde, U. (2018). J. Appl. Crystallogr. Submitted
Keywords: quantum mechanics, refinement