Application of quantum mechanics/molecular mechanics methods in the study of enzymatic reaction mechanisms

Abstract

Quantum mechanics/molecular mechanics (QM/MM) methods offer a very appealing option for the computational study of enzymatic reaction mechanisms, by separating the problem into two parts that can be treated with different computational methods. Hence, in a QM/MM formalism, the part of the system in which catalysis actually occurs and that involves the active site, substrates and directly participating amino acid residues is treated at an adequate quantum mechanical level to describe the chemistry taking place. For the remaining of the enzyme, which does not participate directly in the reaction, but that typically involves a much larger number of atoms, molecular mechanics is employed, traditionally through the application of a biomolecular force field. When applied with care, QM/MM methods can be used with great advantage in comparing, at a structural and energetic level, different mechanistic proposals, discarding mechanistic alternatives and proposing new mechanistic pathways that are consistent with the available experimental data. With time, diverse flavors within the QM/MM methods have emerged, differing in a variety of technical and conceptual aspects. Hence present alternatives differ between additive and subtractive QM/MM schemes, the type of boundary schemes, and the way in which the electrostatic interactions between the two regions are accounted for. Also, single‐conformation QM/MM, multi‐PES approaches, and QM/MM Molecular Dynamics coexist today, each type with its own advantages and limitations. This review focuses on the application of QM/MM methods in the study of enzymatic reaction mechanisms, briefly presenting also the most important technical aspects involved in these calculations. Particular attention is dedicated to the application of the single‐conformation QM/MM, multi‐PES QM/MM studies, and QM/MM‐FEP methods and to the advantages and disadvantages of the different types of QM/MM. Recent breakthroughs are also introduced. A selection of hand‐picked examples is used to illustrate such features. WIREs Comput Mol Sci 2017, 7:e1281. doi: 10.1002/wcms.1281 This article is categorized under: Structure and Mechanism > Computational Biochemistry and Biophysics Structure and Mechanism > Reaction Mechanisms and Catalysis Electronic Structure Theory > Combined QM/MM Methods

Mechanistic insights on the reduction of glutathione disulfide by protein disulfide isomerase

“…To determine the enzymatic mechanism of hPDI, we used QM/MM calculations with the our own N-layered integrated molecular orbital/molecular mechanics (ONIOM) methodology (80). Nevertheless, several different computational approaches have been widely used to determine enzyme reaction mechanisms (81)(82)(83)(84)(85)(86)(87)(88)(89)(90). We have drawn thermochemical and kinetic insight from single-conformation calculations with the X-ray-based model.…”

“…The mPW1N/ 6-31G(d):FF99SB level of theory was used for all geometry optimizations. Several works have shown that the 6-31G(d) basis is adequate for the purpose (85). Furthermore, a previous study has shown that mPW1N (96)(97)(98)(99)(100)(101) [along with mPW1K (96-100, 102, 103), BB1K (104)(105)(106), and mPWB1K (96-100, 104, 107, 108)] is one of the best density functionals to adequately describe the thermochemistry and kinetics of thiol-disulfide exchange (45).…”

Relevance of Hydrogen Bonds for the Histamine H2 Receptor-Ligand Interactions: A Lesson from Deuteration

“…The effect of the rest of the protein environment was considered with the CPCM implicit solvation model using a dielectric constant of ε = 4.0, as suggested by Himo and co-workers [28], and a dielectric constant of ε = 78.4 for the aqueous solution, all in line with our previous reports [13], where we also demonstrated that a potential increase in the former dielectric constant to ε = 20.0 lowers the accuracy of the obtained results and even predicts wrong trends among ligands. Additionally, in our experience, such a truncated cluster-continuum model of the entire protein turned very useful in rationalizing various aspects of the catalytic activity [29], selectivity [30] and inhibition [31] of the monoamine oxidase family of enzymes, and is broadly used by different groups to decipher various biological phenomena [32][33][34][35][36], which justifies its use here. We note in passing that, despite its practical usefulness, the proposed value of ε = 4 is, in some cases, apparently too small to prevent the proton transfer from protonated to anionic residues, which then occurred spontaneously during the geometry optimization, provided the involved pair is in close vicinity.…”

Projector-Based Embedding Eliminates Density Functional Dependence for QM/MM Calculations of Reactions in Enzymes and Solution

“…Multiple applications have shown that, when applied sensibly and appropriately, QM/MM calculations can provide insight and can make useful predictions, [115][116][117][118] and e.g. identify catalytic interactions 119, 120 .…”