Department of Chemistry, Faculty of Science, University of Kurdistan

Mehdi Irani

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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.

Enhancing the Accuracy of Organic Reaction Modeling through Multiscale Methodologies

https://doi.org/10.1038/s41598-024-67468-x

 

Most organic reactions occur in solution phases. However, modeling solution phases using computational chemistry methods is significantly more complex and demanding compared to vacuum calculations. While QM-only calculations can reproduce the mechanisms of organic reactions, their ability to predict the energetics of these reactions is limited.

In this study, we investigated the application of QM and several variants of multiscale methodologies (QM/MM, QM1/QM2, and QM1/QM2/MM) to evaluate their accuracy and effectiveness in predicting the experimental activation energies of two types of organic reactions. We observed that the activation free energies calculated using a continuum solvation model, based on single-point calculations of QM-only structures, fail to account for solvent effects. On the other hand, special variants of multiscale methods (e.g., QM/MM with a large MM-free region and electrostatic embedding, and QM1/QM2/MM with mechanical embedding) more accurately capture the impact of solvents on activation-free energies.

Furthermore, we introduce a Python code for setting up multiscale calculations with ORCA, which is available on GitHub at https://github.com/iranimehdi/pdbtoORCA.

 

Schematic representations depict the QM, QM1, QM2, MM-active, and MM-fixed regions, along with the excluded portion of the system (shown in white) in various types of multiscale calculations conducted using ORCA.

(a)                                                                                       (b)

Performance of multiscale methods in studying the Claisen rearrangement for (a) absolute ΔG^‡ and (b) the energies adjusted for systematic error (MSE).