Dr. Mehdi Irani, academic web page

Department of Chemistry, Faculty of Science, University of Kurdistan

Mehdi Irani

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Quantum Chemistry

Physical Chemistry I

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QM/MM Study of the Catalytic Reaction of Myrosinase; Importance of Assigning Proper Protonation States of Active-Site Residues

J. Chem. Theory Comput. 2021, 17, 3, 1822–1841

Most PDB files have no hydrogen atoms. These atoms can be added by MM programs or some axillary software. However, a few amino acid residues have more than one protonation state. Hence, the user must assign their protonation states. For example, Glu can be charged protonated on OE1or OE2, Asp can be charged protonated on OD1 or OD2, and His can be protonated on ND1, NE2 or charged (protonated on both ND and NE2). Protonation states of these residues are determined by studying hydrogen-bond patterns, solvent accessibility, and the possible formation of ionic pairs.

We have studied different aspects of the catalytic mechanism of myrosinase using QM/MM calculations and MD simulations. From the methodological point of view, our results indicate that assigning proper protonation states of the active site residues is more important than the size of the QM system. Furthermore, to have a proper QM/MM model for studying enzymatic reactions, protonation states of active site residues must be assigned more carefully using MD simulations or QM/MM calculations.

Our model reproduces the anomeric retaining characteristic of myrosinase, and that ascorbate increases the rate of the catalytic reaction of this enzyme. A water molecule in the active site, positioned by Gln-187, helps the aglycon moiety of the substrate to stabilize a build-up of negative charges during the glycosylation reaction and makes it a better leaving group. Moreover, we studied the effects of a few mutations on the energetics of the myrosinase reaction.

Theoretical study of the Unusual Stereospecificity and the Catalytic Reaction of Glyoxalase I

We have worked on the Glyoxalase I (GlxI) enzyme for seven years, using QM-Cluster, Molecular Dynamics, and hybrid QM/MM methods. GlxI is unique in that it can process both stereoisomers of its chiral substrate (hemithioacetal) but produces only one stereoisomer of the product (S-D-lactoylglutathione). It has been an enigma how the seemingly symmetric active site of GlxI does this. In a series of publications, we solved this problem and showed that it is caused by differences in the flexibility of different parts of the enzyme [1–3]. We also confirmed that one of the active-site glutamate residues is more basic than the other (both glutamates are coordinated to the same metal ion and seemingly have the same chemical environment), confirmed a previously proposed reaction mechanism for the S substrate and proposed a new mechanism for the R substrate [4], studied the two-substrate reaction mechanism of GlxI from humans and corn [5], showed that to investigate the reaction mechanism of stereospecific enzymes such as GlxI, very large QM-cluster models or hybrid QM/MM calculations must be employed [6]. Currently, we are working on the metal preference of GlxI (it is not known why some GlxIs are active with Zn(II) ions, whereas others are active with other metal ions).

[1] S. Jafari, N. Kazemi, U. Ryde, M. Irani, Higher Flexibility of Glu-172 Explains the Unusual Stereospecificity of Glyoxalase I, Inorg. Chem. 57 (2018) 4944–4958. https://doi.org/10.1021/acs.inorgchem.7b03215.

[2] S. Jafari, U. Ryde, M. Irani, Catalytic mechanism of human glyoxalase I studied by quantum-mechanical cluster calculations, J. Mol. Catal. B Enzym. 131 (2016) 18–30. https://doi.org/10.1016/j.molcatb.2016.05.010.

[3] S. Jafari, U. Ryde, M. Irani, QM/MM study of the stereospecific proton exchange of glutathiohydroxyacetone by glyoxalase I, Results Chem. 1 (2019) 100011. https://doi.org/10.1016/j.rechem.2019.100011.

[4] S. Jafari, U. Ryde, A.E.A. Fouda, F.S. Alavi, G. Dong, M. Irani, Quantum Mechanics/Molecular Mechanics Study of the Reaction Mechanism of Glyoxalase I, Inorg. Chem. 59 (2020) 2594–2603. https://doi.org/10.1021/acs.inorgchem.9b03621.

[5] S. Jafari, U. Ryde, M. Irani, Two-Substrate Glyoxalase I Mechanism: A Quantum Mechanics/Molecular Mechanics Study, Inorg. Chem. 60 (2021) 303–314. https://doi.org/10.1021/acs.inorgchem.0c02957.

[6] S. Parvaneh, H. Parsa, M. Irani, Can a quantum mechanical cluster model explain the special stereospecificity of glyoxalase I?, Comput. Theor. Chem. 1188 (2020) 112944. https://doi.org/https://doi.org/10.1016/j.comptc.2020.112944.

Benchmark Study of Redox Potential Calculations for Iron–Sulfur Clusters in Proteins

https://pubs.acs.org/doi/full/10.1021/acs.inorgchem.1c03422

Computational chemistry methods have had limited success in determining the reduction potentials of buried groups in proteins. The accuracy of redox potentials cannot be better than 0.26 V even using all-atom DFT/MD simulations and free-energy perturbation methods. Moreover, different methods produce varying results. In such calculations, the main problem is that redox reactions involve a change in the net charge of the studied system. This results in very large and long-range Coulombic interactions. For example, the change in interaction energy between a site in which the net charge changes by 1 e and an oxygen atom in a water-like environment (with a partial charge of –0.8 electrons) is 222 kJ/mol (2.3 V) at a distance of 5 Å. Previous studies have determined whether computational methods can reproduce a measured redox potential or not. If the calculations are also predictive, it will be more satisfying. The calculation could then be used to determine the redox state of metal centers in proteins or to design new sites with appropriate redox potentials. In this work, we examined the redox potentials of twelve different iron-sulfur clusters in some proteins with 1–4 Fe ions using QM-cluster calculations in a continuum solvent based on QM/MM structures. We also included QTCP (QM/MM thermodynamic cycle perturbation) calculations to study the effect of including dynamics. This study was designed to determine which tested methods are most accurate and if they are accurate enough to be utilized for predictive analyses. Our study shows that the most reliable results are obtained with a large QM system (~300 atoms; however, a smaller, ~150 atoms, QM system can be used for the QM/MM geometry optimization) and a high dielectric constant (80). The B3LYP density functional method produces better results than the TPSS method for absolute redox potentials, and the results are further improved with a larger basis set. On the other hand, for relative redox potentials, the opposite is true. The results are unaffected by the force field (charges in the surroundings) used in QM/MM calculations or whether the protein and solvent outside the QM system are relaxed or fixed at the crystal structure.

Mehdi Irani studied chemistry at the University of Kurdistan (UOK) in Sanandaj, Iran, where he graduated with a BSc degree in chemistry in 2004. In 2003 and 2004, he ranked first among students at the Science Faculty of UOK. He also placed third in the national entrance examination for a master's degree in chemistry (February 2004) among ~8000 applicants. Therefore, he was accepted into a master's degree program at the Sharif University of Technology, Tehran, Iran (the most prestigious university in the country for science and engineering studies). He earned his master's degree in 2006, where he studied the kinetics and mechanisms of a few organic reactions. He applied for a Ph.D. program at Sharif University of Technology the same year. In September 2006, he began a Ph.D. program under the supervision of Professor Mohammad Reza Gholami. As part of his Ph.D. program, he had the opportunity to work as a guest student at Lund University in Lund, Sweden, under the supervision of Prof. Ulf Ryde. He obtained his Ph.D. in theoretical chemistry in 2010, emphasizing organic and biomolecular reactions kinetics and mechanisms. After obtaining his doctorate, he began working at UOK as a lecturer. He currently holds the position of Associate Professor at UOK. As a professor at UOK since 2010, he has been teaching Chemical Kinetics, Quantum Chemistry, Physical Chemistry, Computer for Chemistry Students and General Chemistry. As a theoretical chemist, he is primarily interested in enzymatic reactions.