QM/MM study of the mechanism of reduction of 3-hydroxy-3-methylglutaryl coenzyme A catalyzed by human HMG-CoA reductase

Oliveira, Eduardo F.; Cerqueira, Nuno M. F. S. A.; Ramos, María J.; Fernandes, Pedro A.

doi:10.1039/c6cy00356g

Cited by 21 publications

(37 citation statements)

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“…During recent years, Ramos and coworkers have investigated the reaction mechanisms of a large number of enzymes by employing mostly the B3LYP and M06 functionals with/out dispersion corrections in hybrid QM/MM methods . Here, we focus our attention on some of their works in which several density functionals and/or basis sets were tested, to see how they affect the accuracy of the properties such as activation barriers and reaction energies.…”

Section: Models and Methodologiesmentioning

confidence: 99%

Multiscale modeling of enzymes: QM‐cluster, QM/MM, and QM/MM/MD: A tutorial review

Ahmadi

Herrera

Chehelamirani

et al. 2018

Int J of Quantum Chemistry

146

149

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Section: Models and Methodologiesmentioning

confidence: 99%

Multiscale modeling of enzymes: QM‐cluster, QM/MM, and QM/MM/MD: A tutorial review

Ahmadi

Herrera

Chehelamirani

et al. 2018

Int J of Quantum Chemistry

146

149

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“…In a more recent study on the catalytic mechanism of human HMG‐CoA reductase, we chose 15 representative structures along a MD simulation to repeat the reaction path. Structures were initially clustered based on the position of residues in the active center.…”

Section: Improving Sampling: Beyond Single‐conformation Qm/mm Methodsmentioning

confidence: 99%

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

Sousa

Ribeiro

Neves

et al. 2016

WIREs Comput Mol Sci

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157

118

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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

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“…The conclusion is consistent with other previous studies, where low-energy barriers were not found in the majority of the explored conformations but still in a very reasonable number of cases. 7,8,49 In analogy to the concept of "static/dynamic/instantaneous disorder" coined in the past for the dispersion in k cat arising from folding uctuations at several timescales, [50][51][52][53] we refer to the phenomenon seen herein as "chemical disorder", with the adjective "instantaneous" due to the nanosecond timescale in which it takes place.…”

Section: Spread Of the Activation Barriers And Chemical Disordermentioning

confidence: 99%

Conformational diversity induces nanosecond-timescale chemical disorder in the HIV-1 protease reaction pathway

2019

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QM/MM study of the mechanism of reduction of 3-hydroxy-3-methylglutaryl coenzyme A catalyzed by human HMG-CoA reductase

Abstract: Detailing with atomistic resolution the reaction mechanism of human HMG-CoA reductase (HMG-CoA-R) might provide valuable insights for the development of new cholesterol-lowering drugs.

Cited by 21 publications

References 58 publications

Multiscale modeling of enzymes: QM‐cluster, QM/MM, and QM/MM/MD: A tutorial review

Multiscale modeling of enzymes: QM‐cluster, QM/MM, and QM/MM/MD: A tutorial review

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

Conformational diversity induces nanosecond-timescale chemical disorder in the HIV-1 protease reaction pathway

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