Modern non-polarizable force fields diverge in modeling the enzyme–substrate complex of a canonical serine protease

Belyaeva, Julia; Zlobin, Alexander; Maslova, Valentina; Golovin, Andrey V.

doi:10.1039/d2cp05502c

Cited by 3 publications

(3 citation statements)

References 67 publications

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“…Diakamph (V) and moxonidine (VI) were obtained from PubChem database, 51 the other substances were constructed using Yasara program, 52 and their geometric optimization was performed using AMBER 15 IPQ method program, 53 which includes geometric optimization in a water box with alternating sessions of molecular dynamics to select the most stable conformer with minimum energy. Protein obtained from PDB database ( https://www.rcsb.org/ ): model monoamine oxidase-B (2BK3) in complex with the agonist farnesol, monoamine oxidase B in complex with the agonist (2-benzofuranyl)-2-imidazoline (2XCG), chicken brain creatinine kinase (1QH4) and human discharging PX-domain (3P0C).…”

Section: Methodsmentioning

confidence: 99%

Molecular Modeling, Synthesis, and Antihyperglycemic Activity of the New Benzimidazole Derivatives – Imidazoline Receptor Agonists

Martynov,

Farber,

Bomko

et al. 2024

DDDT

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Introduction The paper presents the results of a study on the first synthesized benzimidazole derivatives obtained from labile nature carboxylic acids. The synthesis conditions of these substances were studied, their structure was proved, and some components were found to have sugar-reducing activity on the model of alloxan diabetes in rats. Methods The study used molecular modeling methods such as docking based on the evolutionary model (igemdock), RP_HPLC method to monitor the synthesis reaction, and 1H NMR and 13C NMR, and other methods of organic chemistry to confirm the structures of synthesized substances. Results & Discussion The docking showed that the ursodeoxycholic acid benzimidazole derivatives have high tropics to all imidazoline receptor carriers (PDB ID: 2XCG, 2bk3, 3p0c, 1QH4). The ursodeoxycholic acid benzimidazole derivative and arginine and histidine benzimidazole derivatives showed the highest sugar-lowering activity in the experiment on alloxan-diabetic rats. For these derivatives, the difference in glucose levels of treated rats was significant against untreated control. Therefore, the new derivatives of benzimidazole and labile natural organic acids can be used to create new classes of imidazoline receptor inhibitors for the treatment of diabetes mellitus and hypertension.

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Section: Methodsmentioning

confidence: 99%

Molecular Modeling, Synthesis, and Antihyperglycemic Activity of the New Benzimidazole Derivatives – Imidazoline Receptor Agonists

Martynov,

Farber,

Bomko

et al. 2024

DDDT

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show abstract

“…Individual assignments are accessible as Tables S4 and S5 in Data S1 . Models were parameterized with the Amber ff99SB‐ildn (Belyaeva et al, 2023 ; Lindorff‐Larsen et al, 2010 ). Parameters for the DEP serine were based on parameterize (Galvelis et al, 2019 ) QM scans for the triethyl‐phosphate moiety similarly to what was done before (Zlobin et al, 2021 ).…”

Section: Methodsmentioning

confidence: 99%

Dynamic interchange between two protonation states is characteristic of active sites of cholinesterases

Zlobin,

Smirnov,

Golovin

2024

Protein Science

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Cholinesterases are well‐known and widely studied enzymes crucial to human health and involved in neurology, Alzheimer's, and lipid metabolism. The protonation pattern of active sites of cholinesterases influences all the chemical processes within, including reaction, covalent inhibition by nerve agents, and reactivation. Despite its significance, our comprehension of the fine structure of cholinesterases remains limited. In this study, we employed enhanced‐sampling quantum‐mechanical/molecular‐mechanical calculations to show that cholinesterases predominantly operate as dynamic mixtures of two protonation states. The proton transfer between two non‐catalytic glutamate residues follows the Grotthuss mechanism facilitated by a mediator water molecule. We show that this uncovered complexity of active sites presents a challenge for classical molecular dynamics simulations and calls for special treatment. The calculated proton transfer barrier of 1.65 kcal/mol initiates a discussion on the potential existence of two coupled low‐barrier hydrogen bonds in the inhibited form of butyrylcholinesterase. These findings expand our understanding of structural features expressed by highly evolved enzymes and guide future advances in cholinesterase‐related protein and drug design studies.

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“…Models were parameterized with the Amber ff99SB-ildn 40 force field chosen based on our previous findings for enzymatic systems. 41 Diethyl-phosphorylated (DEP) serine was parameterized as a single residue by combining force-field Ser parameters with ones derived for a triethyl-phosphate moiety. It was done with the parameterize tool by tailoring GAFF2 torsions towards QM scans on the wB97X-D level of theory with aug-cc-pVDZ basis set 42 similarly to what was done before.…”

Section: System Preparation and Classical MDmentioning

confidence: 99%

Dynamic Interchange Between Two Protonation States is Characteristic of Active Sites of Cholinesterases

Zlobin,

Smirnov,

Golovin

2024

Preprint

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Cholinesterases are well-known and widely studied enzymes crucial to human health and involved in neurology, Alzheimer, and lipid metabolism. The protonation pattern of cholinesterases’ active sites influences all the chemical processes within, including reaction, covalent inhibition by nerve agents, and reactivation. Our understanding of it is, however, limited. In this study, we used enhanced-sampling quantum-mechanical/molecular-mechanical calculations to show that cholinesterases mostly function as dynamical mixtures of two protonation states. Proton transfer between two non-catalytic glutamate residues occurs by Grotthuss mechanism via a mediator water molecule. We show that this uncovered complexity of active sites presents a challenge for classical molecular dynamics simulations that calls for special treatment. The proton transfer barrier of 1.65 kcal/mol opens the discussion on potential existence of two conjugated low barrier hydrogen bonds in the inhibited form of butyrylcholinesterase. These findings expand our understanding of structural features expressed by highly evolved enzymes and guide future advances in cholinesterase-related protein- and drug design studies.

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Modern non-polarizable force fields diverge in modeling the enzyme–substrate complex of a canonical serine protease

Abstract: Classical molecular dynamics simulation is a powerful and established method of modern computational chemistry. Being able to obtain accurate information on molecular behavior is crucial to get valuable insights into...

Cited by 3 publications

References 67 publications

Molecular Modeling, Synthesis, and Antihyperglycemic Activity of the New Benzimidazole Derivatives – Imidazoline Receptor Agonists

Molecular Modeling, Synthesis, and Antihyperglycemic Activity of the New Benzimidazole Derivatives – Imidazoline Receptor Agonists

Dynamic interchange between two protonation states is characteristic of active sites of cholinesterases

Dynamic Interchange Between Two Protonation States is Characteristic of Active Sites of Cholinesterases

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