Semiempirical QM/MM potential with simple valence bond (SVB) for enzyme reactions. Application to the nucleophilic addition reaction in haloalkane dehalogenase

Devi-Kesavan, Lakshmi S.; Garcia‐Viloca, Mireia; Gao, Jiali

doi:10.1007/s00214-002-0419-x

Cited by 31 publications

(2 citation statements)

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“…We performed an interaction-energy decomposition analysis at the reactant state (R) and the transition state (TS3) of the rate-limiting step using the combined QM/MM potential. This approach has been widely used in various other enzyme systems to address the roles of amino-acid residues in stabilizing (or destabilizing) the transition state. ,− Among the selected structures in each state, for each configuration, we sequentially zeroed the MM charges of the amino-acid residues in the HTLV-1 protease in the order of the shortest distance from the carbonyl carbon (C, labeled in Figure ) of the scissile bond on the substrate to the C α atom of a residue. For each selected residue, the difference in the QM electrostatic energy before and after the charge annihilation was calculated.…”

Section: Resultsmentioning

confidence: 99%

Catalytic Mechanism of Human T-Cell Leukemia Virus Type 1 Protease Investigated by Combined QM/MM Molecular Dynamics Simulations

Petrillo

Dinh

Vogt

et al. 2023

J. Chem. Inf. Model.

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Combined quantum mechanical and molecular mechanical (QM/MM) molecular dynamics simulations were performed to investigate the catalytic mechanism of human T-cell leukemia virus type 1 (HTLV-1) protease, a retroviral aspartic protease that is a potential therapeutic target for curing HTLV-1-associated diseases. To elucidate the proteolytic cleavage mechanism, we determined the two-dimensional free energy surfaces of the HTLV-1 protease-catalyzed reactions through various possible pathways. The free energy simulations suggest that the catalytic reactions of the HTLV-1 protease occur in the following sequential steps: (1) a proton is transferred from the lytic water to Asp32′, followed by the nucleophilic addition of the resulting hydroxyl to the carbonyl carbon of the scissile bond, forming a tetrahedral oxyanion intermediate, and (2) a proton is transferred from Asp32 to the peptide nitrogen of the scissile bond, leading to the spontaneous breakage of the scissile bond. The rate-limiting step of this catalytic process is the proton transfer from Asp32 to the peptide nitrogen of the scissile bond, with a free energy of activation of 21.1 kcal/mol. This free energy barrier is close to the experimentally determined free energy of activation (16.3 kcal/mol) calculated from the measured catalytic rate constant (k cat). This mechanistic study provides detailed dynamic and structural information that will facilitate the design of mechanism-based inhibitors for the treatment of HTLV-1-associated diseases.

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Section: Resultsmentioning

confidence: 99%

Catalytic Mechanism of Human T-Cell Leukemia Virus Type 1 Protease Investigated by Combined QM/MM Molecular Dynamics Simulations

Petrillo

Dinh

Vogt

et al. 2023

J. Chem. Inf. Model.

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“…These hybrid methods are typically orders of magnitudes more efficient than fully quantum mechanical approaches, although recent advances in the development of reactive quantum mechanical force fields have greatly narrowed this gap. [1][2][3][4] QM/MM methods have been successfully applied in the study of enzymes, [5][6][7] catalytic RNAs, [8][9][10] ligand binding, [11][12][13] acid dissociation constants, [14][15][16] and small molecule reactions occurring in solution. [17][18][19][20] Combined QM/MM approaches leverage the strengths associated with of both QM methods and MM simulations by allowing a typically small, localized reactive region requiring explicit treatment of electronic degrees of freedom to be modeled within a large, complex condensed phase environment.…”

Section: Introductionmentioning

confidence: 99%

Charge-dependent many-body exchange and dispersion interactions in combined QM/MM simulations

Kuechler

Giese

York

2015

The Journal of Chemical Physics

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Accurate modeling of the molecular environment is critical in condensed phase simulations of chemical reactions. Conventional quantum mechanical/molecular mechanical (QM/MM) simulations traditionally model non-electrostatic non-bonded interactions through an empirical Lennard-Jones (LJ) potential which, in violation of intuitive chemical principles, is bereft of any explicit coupling to an atom's local electronic structure. This oversight results in a model whereby short-ranged exchange-repulsion and long-ranged dispersion interactions are invariant to changes in the local atomic charge, leading to accuracy limitations for chemical reactions where significant atomic charge transfer can occur along the reaction coordinate. The present work presents a variational, charge-dependent exchange-repulsion and dispersion model, referred to as the charge-dependent exchange and dispersion (QXD) model, for hybrid QM/MM simulations. Analytic expressions for the energy and gradients are provided, as well as a description of the integration of the model into existing QM/MM frameworks, allowing QXD to replace traditional LJ interactions in simulations of reactive condensed phase systems. After initial validation against QM data, the method is demonstrated by capturing the solvation free energies of a series of small, chlorine-containing compounds that have varying charge on the chlorine atom. The model is further tested on the SN2 attack of a chloride anion on methylchloride. Results suggest that the QXD model, unlike the traditional LJ model, is able to simultaneously obtain accurate solvation free energies for a range of compounds while at the same time closely reproducing the experimental reaction free energy barrier. The QXD interaction model allows explicit coupling of atomic charge with many-body exchange and dispersion interactions that are related to atomic size and provides a more accurate and robust representation of non-electrostatic non-bonded QM/MM interactions.

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The Empirical Valence Bond ( EVB ) Method

Warshel

Florián

1998

Encyclopedia of Computational Chemistry

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The empirical valence bond (EVB) model is a powerful conceptual and practical tool for studies of reactions of complex systems, ranging from reactions of large molecules to chemical processes in solutions and in enzymes. This method that can be viewed as an extension of force‐field approaches to chemical reactivity is related here to other hybrid quantum mechanical/molecular mechanics (QM/MM) methods and to other approaches. The review starts by pointing out the relationship between the EVB and early VB concepts. It is noted that while the VB models were developed for studies of chemical bonding in small molecules, the EVB models have provided a general and uniform way of simulating chemical reactions in large molecules and molecules in any environment. The use of the EVB approach in modeling chemical reactions is reviewed, emphasizing the effectiveness of the method in studies of enzyme catalysis. The advantages of the EVB approach are also considered, pointing out the usefulness of the analytical form of this method and its crucial importance for molecular dynamics simulations and free energy calculations of processes in condensed phases. Finally, the current proliferation of the EVB approach and its emergence under different names is discussed, clarifying the relationship between the different EVB–type models.

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Semiempirical QM/MM potential with simple valence bond (SVB) for enzyme reactions. Application to the nucleophilic addition reaction in haloalkane dehalogenase

Cited by 31 publications

References 1 publication

Catalytic Mechanism of Human T-Cell Leukemia Virus Type 1 Protease Investigated by Combined QM/MM Molecular Dynamics Simulations

Catalytic Mechanism of Human T-Cell Leukemia Virus Type 1 Protease Investigated by Combined QM/MM Molecular Dynamics Simulations

Charge-dependent many-body exchange and dispersion interactions in combined QM/MM simulations

The Empirical Valence Bond ( EVB ) Method

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