In this webinar, I will discuss our approach to performing QM/MM calculations [1, 2], emphasizing three aspects of QM/MM calculations we have developed in our group.
The first is the combination of QM/MM calculations with experimental raw data in the form of X-ray or neutron crystallography, NMR or EXAFS measurements [3–6]. This has turned out to be a powerful approach to improve structures, determine what is really seen in the structures and settle protonation and oxidation states [7–10].
The second is the bigQM approach, in which we try to converge the energies with respect to the size of the QM system by performing single-point energy calculations including all residues within 4.5–6 Å of a minimal QM system, all buried charges in the protein and moving cut bonds at least three residues away from the active site, in total typically ~1000 atoms [11, 12].
The third is to calculate QM/MM free energies without actually performing QM/MM molecular dynamics simulations with the reference-potential approach [13, 14].
Prof. Ulf Ryde Lund University
Ulf Ryde received his Ph.D. in biochemistry from Lund University, Sweden, under the supervision of Prof. G. Pettersson in 1991. He then moved into the field of theoretical chemistry at the same university as a postdoctoral fellow of Prof. Björn Roos. He became a docent in 1996 and a full professor in 2004. From 2001 to 2007 he had a senior research position at the Swedish Research Council. He has published ~270 papers. He studies the structure and function of proteins, in particular metalloproteins, such as blue copper proteins, heme enzymes, vitamin B12 enzymes, hydrogenases, multicopper oxidases and nitrogenase. He has developed QM/MM methods for an accurate treatment of environmental effects, e.g., using accurate MM force fields with multipole expansions and anisotropic polarization, and combinations of QM/MM with free-energy methods or experimental approaches, such as X-ray crystallography, NMR, and extended X-ray absorption fine structure (EXAFS) spectroscopy. He also studies and develops methods to calculate ligand-binding affinities, in particular with free-energy simulations, as well as various combinations of MM and QM methods.
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 Ryde U (2016) QM/MM Calculations on Proteins. Methods Enzymol 577:119–158. https://doi.org/10.1016/bs.mie.2016.05.014  Cao L, Ryde U (2018) On the difference between additive and subtractive QM/MM calculations. Front Chem 6:89. https://doi.org/10.3389/fchem.2018.00089  Ryde U, Olsen L, Nilsson K (2002) Quantum chemical geometry optimizations in proteins using crystallographic raw data. J Comput Chem 23:1058–1070. https://doi.org/10.1002/jcc.10093  Hsiao Y, Drakenberg T, Ryde U (2005) NMR structure determination of proteins supplemented by quantum chemical calculations: Detailed structure of the Ca2+ sites in the EGF34 fragment of protein S. J Biomol NMR 31:97–114. https://doi.org/10.1007/s10858-004-6729-7  Hsiao Y, Tao Y, Shokes JE, et al (2006) EXAFS structure refinement supplemented by computational chemistry. Phys Rev B 74:214101. https://doi.org/10.10.1103/PhysRevB.74.214101  Caldararu O, Manzoni F, Oksanen E, et al (2019) Refinement of protein structures using a combination of quantum-mechanical calculations with neutron and X-ray crystallographic data. Acta Crystallogr Sect D Biol Crystallogr 75:368–380  Ryde U, Nilsson K (2003) Quantum Chemistry Can Locally Improve Protein Crystal Structures. J Am Chem Soc 125:14232–14233. https://doi.org/10.1021/ja0365328  Nilsson K, Ryde U (2004) Protonation status of metal-bound ligands can be determined by quantum refinement. J Inorg Biochem 98:1539–1546. https://doi.org/10.1016/j.jinorgbio.2004.06.006  Söderhjelm P, Ryde U (2006) Combined computational and crystallographic study of the oxidised states of [NiFe] hydrogenase. J Mol Struct THEOCHEM 770:199–219. https://doi.org/10.1016/j.theochem.2006.06.008  Cao L, Caldararu O, Rosenzweig AC, Ryde U (2018) Quantum Refinement Does Not Support Dinuclear Copper Sites in Crystal Structures of Particulate Methane Monooxygenase. Angew Chemie – Int Ed 57:162–166. https://doi.org/10.1002/anie.201708977  Hu L, Söderhjelm P, Ryde U (2013) Accurate reaction energies in proteins obtained by combining QM/MM and large QM calculations. J Chem Theory Comput 9:640–649. https://doi.org/10.1021/ct3005003  Sumner S, Söderhjelm P, Ryde U (2013) Effect of Geometry Optimizations on QM-Cluster and QM/MM Studies of Reaction Energies in Proteins. J Chem Theory Comput 9:4205–4214. https://doi.org/10.1021/ct400339c  Rod TH, Ryde U (2005) Accurate QM/MM free energy calculations of enzyme reactions: Methylation by catechol O-methyltransferase. J Chem Theory Comput 1:1240–1251. https://doi.org/10.1021/ct0501102  Olsson MA, Ryde U (2017) Comparison of QM/MM Methods To Obtain Ligand-Binding Free Energies. J Chem Theory Comput 13:2245–2253. https://doi.org/10.1021/acs.jctc.6b01217