Light-Induced Change of Arginine Conformation Modulates the Rate of Adenosine Triphosphate to Cyclic Adenosine Monophosphate Conversion in the Optogenetic System Containing Photoactivated Adenylyl Cyclase

Khrenova, Maria G.; Kulakova, A. M.; Nemukhin, Alexander V.

doi:10.1021/acs.jcim.0c01308

Cited by 18 publications

(16 citation statements)

References 68 publications

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“…Figure 1 illustrates an arrangement of molecular groups in the active site of the Arl3-RP2-GTP-H 2 O structure in the vicinity of the ES complex. Previous experience in theoretical studies of enzyme-catalyzed reactions [ 15 , 16 , 17 ] shows that dynamics of ES is an essential issue, which helps us to recognize reactive conformations of the system. Therefore, we analyze dynamical properties of ES complexes along MD trajectories calculated with the QM/MM potentials, also paying attention to the choice of the DFT functional in QM.…”

Section: Resultsmentioning

confidence: 99%

“…It is feasible to apply atom-centered basis sets of 6-31G** or cc-pvdz quality and to use a variety of hybrid functionals of the density functional theory (DFT) in calculations of energies and forces in QM parts and commonly accepted force field parameters in MM parts. When computing MD trajectories of about 10 ps length per window, it is possible to apply the umbrella sampling (US) scan of the Gibbs energy surface with the subsequent statistical analysis, using umbrella integration (UI) methods [ 13 , 14 ] to quantify elementary steps of chemical reactions in the enzyme active sites, for example, [ 15 , 16 , 17 ].…”

Section: Introductionmentioning

confidence: 99%

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Mechanism of Guanosine Triphosphate Hydrolysis by the Visual Proteins Arl3-RP2: Free Energy Reaction Profiles Computed with Ab Initio Type QM/MM Potentials

et al. 2021

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We report the results of calculations of the Gibbs energy profiles of the guanosine triphosphate (GTP) hydrolysis by the Arl3-RP2 protein complex using molecular dynamics (MD) simulations with ab initio type QM/MM potentials. The chemical reaction of GTP hydrolysis to guanosine diphosphate (GDP) and inorganic phosphate (Pi) is catalyzed by GTPases, the enzymes, which are responsible for signal transduction in live cells. A small GTPase Arl3, catalyzing the GTP → GDP reaction in complex with the activating protein RP2, constitute an essential part of the human vision cycle. To simulate the reaction mechanism, a model system is constructed by motifs of the crystal structure of the Arl3-RP2 complexed with a substrate analog. After selection of reaction coordinates, energy profiles for elementary steps along the reaction pathway GTP + H2O → GDP + Pi are computed using the umbrella sampling and umbrella integration procedures. QM/MM MD calculations are carried out, interfacing the molecular dynamics program NAMD and the quantum chemistry program TeraChem. Ab initio type QM(DFT)/MM potentials are computed with atom-centered basis sets 6-31G** and two hybrid functionals (PBE0-D3 and ωB97x-D3) of the density functional theory, describing a large QM subsystem. Results of these simulations of the reaction mechanism are compared to those obtained with QM/MM calculations on the potential energy surface using a similar description of the QM part. We find that both approaches, QM/MM and QM/MM MD, support the mechanism of GTP hydrolysis by GTPases, according to which the catalytic glutamine side chain (Gln71, in this system) actively participates in the reaction. Both approaches distinguish two parts of the reaction: the cleavage of the phosphorus-oxygen bond in GTP coupled with the formation of Pi, and the enzyme regeneration. Newly performed QM/MM MD simulations confirmed the profile predicted in the QM/MM minimum energy calculations, called here the pathway-I, and corrected its relief at the first elementary step from the enzyme–substrate complex. The QM/MM MD simulations also revealed another mechanism at the part of enzyme regeneration leading to pathway-II. Pathway-II is more consistent with the experimental kinetic data of the wild-type complex Arl3-RP2, whereas pathway-I explains the role of the mutation Glu138Gly in RP2 slowing down the hydrolysis rate.

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Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Mechanism of Guanosine Triphosphate Hydrolysis by the Visual Proteins Arl3-RP2: Free Energy Reaction Profiles Computed with Ab Initio Type QM/MM Potentials

et al. 2021

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“…Figures S2 and S3 depict distributions obtained with different harmonic potentials. MD trajectories of the comparable lengths were calculated in other enzymatic reaction mechanism studies; see, for example, ref [59]. Additional 10 ps runs were performed for the ES complex and E•cpd5 with the ξ0 = 10.1 Å and K = 40 kcal/(mol•Å 2 ) harmonic potential.…”

Section: Models and Methodsmentioning

confidence: 99%

“…It means that not all ES complexes (frames along the MD trajectory) correspond to the reactive species. The fraction with the larger f+ values demonstrates the substrate activation in the active site of the enzyme discussed in Refs [59,69]. The Gibbs energy profile for the nucleophilic attack step was calculated using the umbrella sampling technique (Figure 5).…”

Section: Imipenem and Boronic Acid Inhibitor Cpd5 In Water Solution And In The Active Site Of Ndm-1mentioning

confidence: 99%

Boronic Acids as Prospective Inhibitors of Metallo-β-Lactamases: Efficient Chemical Reaction in the Enzymatic Active Site Revealed by Molecular Modeling

Krivitskaya

Khrenova

2021

Molecules

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Boronic acids are prospective compounds in inhibition of metallo-β-lactamases as they form covalent adducts with the catalytic hydroxide anion in the enzymatic active site upon binding. We compare this chemical reaction in the active site of the New Delhi metallo-β-lactamase (NDM-1) with the hydrolysis of the antibacterial drug imipenem. The nucleophilic attack occurs with the energy barrier of 14 kcal/mol for imipenem and simultaneously upon binding a boronic acid inhibitor. A boron atom of an inhibitor exhibits stronger electrophilic properties than the carbonyl carbon atom of imipenem in a solution that is quantified by atomic Fukui indices. Upon forming the prereaction complex between NDM-1 and inhibitor, the lone electron pair of the nucleophile interacts with the vacant p-orbital of boron that facilitates the chemical reaction. We analyze a set of boronic acid compounds with the benzo[b]thiophene core complexed with the NDM-1 and propose quantitative structure-sroperty relationship (QSPR) equations that can predict IC50 values from the calculated descriptors of electron density. These relations are applied to classify other boronic acids with the same core found in the database of chemical compounds, PubChem, and proposed ourselves. We demonstrate that the IC50 values for all considered benzo[b]thiophene-containing boronic acid inhibitors are 30–70 μM.

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“…When computing MD trajectories of about 10 ps length per window, it is possible to apply the umbrella sampling (US) scan of the Gibbs energy surface with the subsequent statistical analysis, using umbrella integration (UI) methods [22,23] to quantify elementary steps of chemical reactions in the enzyme active sites (see, for example, Refs. [24][25][26][27][28]). Using this technique, we are able to construct reaction energy profiles with realistic barrier heights on the reaction pathway.…”

Section: Gcpiimentioning

confidence: 99%

Two Sides of Quantum-Based Modeling of Enzyme-Catalyzed Reactions: Mechanistic and Electronic Structure Aspects of the Hydrolysis by Glutamate Carboxypeptidase

2021

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We report the results of a computational study of the hydrolysis reaction mechanism of N-acetyl-l-aspartyl-l-glutamate (NAAG) catalyzed by glutamate carboxypeptidase II. Analysis of both mechanistic and electronic structure aspects of this multistep reaction is in the focus of this work. In these simulations, model systems are constructed using the relevant crystal structure of the mutated inactive enzyme. After selection of reaction coordinates, the Gibbs energy profiles of elementary steps of the reaction are computed using molecular dynamics simulations with ab initio type QM/MM potentials (QM/MM MD). Energies and forces in the large QM subsystem are estimated in the DFT(PBE0-D3/6-31G**) approximation. The established mechanism includes four elementary steps with the activation energy barriers not exceeding 7 kcal/mol. The models explain the role of point mutations in the enzyme observed in the experimental kinetic studies; namely, the Tyr552Ile substitution disturbs the “oxyanion hole”, and the Glu424Gln replacement increases the distance of the nucleophilic attack. Both issues diminish the substrate activation in the enzyme active site. To quantify the substrate activation, we apply the QTAIM-based approaches and the NBO analysis of dynamic features of the corresponding enzyme-substrate complexes. Analysis of the 2D Laplacian of electron density maps allows one to define structures with the electron density deconcentration on the substrate carbon atom, i.e., at the electrophilic site of reactants. The similar electronic structure element in the NBO approach is a lone vacancy on the carbonyl carbon atom in the reactive species. The electronic structure patterns revealed in the NBO and QTAIM-based analyses consistently clarify the reactivity issues in this system.

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Light-Induced Change of Arginine Conformation Modulates the Rate of Adenosine Triphosphate to Cyclic Adenosine Monophosphate Conversion in the Optogenetic System Containing Photoactivated Adenylyl Cyclase

Cited by 18 publications

References 68 publications

Mechanism of Guanosine Triphosphate Hydrolysis by the Visual Proteins Arl3-RP2: Free Energy Reaction Profiles Computed with Ab Initio Type QM/MM Potentials

Mechanism of Guanosine Triphosphate Hydrolysis by the Visual Proteins Arl3-RP2: Free Energy Reaction Profiles Computed with Ab Initio Type QM/MM Potentials

Boronic Acids as Prospective Inhibitors of Metallo-β-Lactamases: Efficient Chemical Reaction in the Enzymatic Active Site Revealed by Molecular Modeling

Two Sides of Quantum-Based Modeling of Enzyme-Catalyzed Reactions: Mechanistic and Electronic Structure Aspects of the Hydrolysis by Glutamate Carboxypeptidase

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