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Molecular Modeling: Insights into the Enzymatic Reactions and Photochemical Processes in Biomacromolecules

A special issue of Molecules (ISSN 1420-3049). This special issue belongs to the section "Photochemistry".

Deadline for manuscript submissions: closed (28 February 2023) | Viewed by 12949

Special Issue Editor

Prof. Dr. Maria G. Khrenova

E-Mail Website
Guest Editor
1. Department of Chemistry, Lomonosov Moscow State University, Moscow, Russia
2. Bach Institute of Biochemistry, Federal Research Centre “Fundamentals of Biotechnology” of the Russian Academy of Sciences, Moscow, Russia
Interests: molecular modeling; computational and quantum chemistry; enzymatic reactions; photochemistry; QM/MM
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

The molecular modeling of biochemistry-related processes is a rapidly developing field. Recent advancements in QM/MM methods and molecular dynamic simulations, as well as the development of computers and software, make it possible to obtain qualitative and quantitative models. The mechanisms of many enzymatic reactions and photochemical processes are already established. Nevertheless, there is a huge number of questions that remain unanswered. Moreover, the accumulation of novel experimental data requires its explanation from the mechanistic viewpoint. Modern molecular modeling aims to explain experimental observations and to predict novel compounds or biomacromolecular systems with the desired properties. A novel direction in the molecular modeling of biochemical processes is related to the electron density analysis of enzymatic active sites or chromophore binding pockets, which gives additional insight into the reaction mechanism.

The aim of this Special Issue is to highlight recent advancements in molecular modeling related to biomolecular processes. Contributions that cover all of these topics, as well as combined theoretical and experimental studies, are highly encouraged.

Prof. Dr. Maria G. Khrenova
Guest Editor

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Keywords

  • molecular modeling
  • QM/MM
  • molecular dynamics
  • DFT
  • enzymatic reactions
  • photoreceptor proteins
  • fluorescent proteins
  • substrate specificity
  • enzyme-inhibitor complexes

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Published Papers (5 papers)

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Research

17 pages, 9287 KiB  
Article
QM/MM Modeling of the Flavin Functionalization in the RutA Monooxygenase
by Bella Grigorenko, Tatiana Domratcheva and Alexander Nemukhin
Molecules 2023, 28(5), 2405; https://doi.org/10.3390/molecules28052405 - 6 Mar 2023
Cited by 2 | Viewed by 2420
Abstract
Oxygenase activity of the flavin-dependent enzyme RutA is commonly associated with the formation of flavin-oxygen adducts in the enzyme active site. We report the results of quantum mechanics/molecular mechanics (QM/MM) modeling of possible reaction pathways initiated by various triplet state complexes of the [...] Read more.
Oxygenase activity of the flavin-dependent enzyme RutA is commonly associated with the formation of flavin-oxygen adducts in the enzyme active site. We report the results of quantum mechanics/molecular mechanics (QM/MM) modeling of possible reaction pathways initiated by various triplet state complexes of the molecular oxygen with the reduced flavin mononucleotide (FMN) formed in the protein cavities. According to the calculation results, these triplet-state flavin-oxygen complexes can be located at both re-side and si-side of the isoalloxazine ring of flavin. In both cases, the dioxygen moiety is activated by electron transfer from FMN, stimulating the attack of the arising reactive oxygen species at the C4a, N5, C6, and C8 positions in the isoalloxazine ring after the switch to the singlet state potential energy surface. The reaction pathways lead to the C(4a)-peroxide, N(5)-oxide, or C(6)-hydroperoxide covalent adducts or directly to the oxidized flavin, depending on the initial position of the oxygen molecule in the protein cavities. Full article
(This article belongs to the Special Issue Molecular Modeling: Insights into the Enzymatic Reactions and Photochemical Processes in Biomacromolecules)
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21 pages, 3661 KiB  
Article
To the Understanding of Catalysis by D-Amino Acid Transaminases: A Case Study of the Enzyme from Aminobacterium colombiense
by Sofia A. Shilova, Maria G. Khrenova, Ilya O. Matyuta, Alena Y. Nikolaeva, Tatiana V. Rakitina, Natalia L. Klyachko, Mikhail E. Minyaev, Konstantin M. Boyko, Vladimir O. Popov and Ekaterina Yu. Bezsudnova
Molecules 2023, 28(5), 2109; https://doi.org/10.3390/molecules28052109 - 23 Feb 2023
Cited by 9 | Viewed by 3158
Abstract
Pyridoxal-5′-phosphate (PLP)-dependent transaminases are highly efficient biocatalysts for stereoselective amination. D-amino acid transaminases can catalyze stereoselective transamination producing optically pure D-amino acids. The knowledge of substrate binding mode and substrate differentiation mechanism in D-amino acid transaminases comes down to the analysis of the [...] Read more.
Pyridoxal-5′-phosphate (PLP)-dependent transaminases are highly efficient biocatalysts for stereoselective amination. D-amino acid transaminases can catalyze stereoselective transamination producing optically pure D-amino acids. The knowledge of substrate binding mode and substrate differentiation mechanism in D-amino acid transaminases comes down to the analysis of the transaminase from Bacillus subtilis. However, at least two groups of D-amino acid transaminases differing in the active site organization are known today. Here, we present a detailed study of D-amino acid transaminase from the gram-negative bacterium Aminobacterium colombiense with a substrate binding mode different from that for the transaminase from B. subtilis. We study the enzyme using kinetic analysis, molecular modeling, and structural analysis of holoenzyme and its complex with D-glutamate. We compare the multipoint binding of D-glutamate with the binding of other substrates, D-aspartate and D-ornithine. QM/MM MD simulation reveals that the substrate can act as a base and its proton can be transferred from the amino group to the α-carboxylate group. This process occurs simultaneously with the nucleophilic attack of the PLP carbon atom by the nitrogen atom of the substrate forming gem-diamine at the transimination step. This explains the absence of the catalytic activity toward (R)-amines that lack an α-carboxylate group. The obtained results clarify another substrate binding mode in D-amino acid transaminases and underpinned the substrate activation mechanism. Full article
(This article belongs to the Special Issue Molecular Modeling: Insights into the Enzymatic Reactions and Photochemical Processes in Biomacromolecules)
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13 pages, 4752 KiB  
Article
Insights into the Formation of Intermolecular Complexes of Fluorescent Probe 10-N-Nonyl Acridine Orange with Cardiolipin and Phosphatidylglycerol in Bacterial Plasma Membrane by Molecular Modeling
by Ekaterina Kholina, Ilya Kovalenko, Andrew Rubin and Marina Strakhovskaya
Molecules 2023, 28(4), 1929; https://doi.org/10.3390/molecules28041929 - 17 Feb 2023
Cited by 4 | Viewed by 2305
Abstract
In this article, we used molecular dynamics (MD), one of the most common methods for simulations of membranes, to study the interaction of fluorescent membranotropic biological probe 10-N-nonyl acridine orange (NAO) with the bilayer, mimicking a plasma membrane of Gram-negative bacteria. [...] Read more.
In this article, we used molecular dynamics (MD), one of the most common methods for simulations of membranes, to study the interaction of fluorescent membranotropic biological probe 10-N-nonyl acridine orange (NAO) with the bilayer, mimicking a plasma membrane of Gram-negative bacteria. Fluorescent probes serve as an effective tool to study the localization of different components in biological membranes. Revealing the molecular details of their interaction with membrane phospholipids is important both for the interpretation of experimental results and future design of lipid-specific stains. By means of coarse-grained (CG) MD, we studied the interactions of NAO with a model membrane, imitating the plasma membrane of Gram-negative bacteria. In our simulations, we detected different NAO forms: monomers, dimers, and stacks. NAO dimers had the central cardiolipin (CL) molecule in a sandwich-like structure. The stacks were formed by NAO molecules interlayered with anionic lipids, predominantly CL. Use of the CG approach allowed to confirm the ability of NAO to bind to both major negatively charged phospholipids, phosphatidylglycerol (PG) and CL, and to shed light on the exact structure of previously proposed NAO–lipid complexes. Thus, CG modeling can be useful for the development of new effective and highly specific molecular probes. Full article
(This article belongs to the Special Issue Molecular Modeling: Insights into the Enzymatic Reactions and Photochemical Processes in Biomacromolecules)
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12 pages, 2853 KiB  
Article
Influence of the Active Site Flexibility on the Efficiency of Substrate Activation in the Active Sites of Bi-Zinc Metallo-β-Lactamases
by Alexandra V. Krivitskaya and Maria G. Khrenova
Molecules 2022, 27(20), 7031; https://doi.org/10.3390/molecules27207031 - 18 Oct 2022
Cited by 3 | Viewed by 2007
Abstract
The influence of the active site flexibility on the efficiency of catalytic reaction is studied by taking two members of metallo-β-lactamases, L1 and NDM-1, with the same substrate, imipenem. Active sites of these proteins are covered by L10 loops, and differences in their [...] Read more.
The influence of the active site flexibility on the efficiency of catalytic reaction is studied by taking two members of metallo-β-lactamases, L1 and NDM-1, with the same substrate, imipenem. Active sites of these proteins are covered by L10 loops, and differences in their amino acid compositions affect their rigidity. A more flexible loop in the NDM-1 brings additional flexibility to the active site in the ES complex. This is pronounced in wider distributions of key interatomic distances, such as the distance of the nucleophilic attack, coordination bond lengths, and covalent bond lengths in the substrate. Substrate activation, quantified by Fukui electrophilicity index of the carbonyl carbon atom of the substrate, is also sensitive to the active site flexibility. In the tighter and more rigid L1 enzyme-substrate complex, the substrate is activated more efficiently. In the NDM-1 containing system, only one third of the states are activated to the same extent. Other fractions demonstrate lower substrate activation. Efficiency of the substrate activation and rigidity of the ES complex influence the following chemical reaction. In the more rigid L1-containing system, the reaction barrier of the first step of the reaction is lower, and the first intermediate is more stabilized compared to the NDM-1 containing system. Full article
(This article belongs to the Special Issue Molecular Modeling: Insights into the Enzymatic Reactions and Photochemical Processes in Biomacromolecules)
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15 pages, 3734 KiB  
Article
Computational Insight into Biotransformation Profiles of Organophosphorus Flame Retardants to Their Diester Metabolites by Cytochrome P450
by Yue Jia, Tingji Yao, Guangcai Ma, Qi Xu, Xianglong Zhao, Hui Ding, Xiaoxuan Wei, Haiying Yu and Zhiguo Wang
Molecules 2022, 27(9), 2799; https://doi.org/10.3390/molecules27092799 - 28 Apr 2022
Cited by 10 | Viewed by 2348
Abstract
Biotransformation of organophosphorus flame retardants (OPFRs) mediated by cytochrome P450 enzymes (CYPs) has a potential correlation with their toxicological effects on humans. In this work, we employed five typical OPFRs including tris(1,3-dichloro-2-propyl) phosphate (TDCIPP), tris(1-chloro-2-propyl) phosphate (TCIPP), tri(2-chloroethyl) phosphate (TCEP), triethyl phosphate (TEP), [...] Read more.
Biotransformation of organophosphorus flame retardants (OPFRs) mediated by cytochrome P450 enzymes (CYPs) has a potential correlation with their toxicological effects on humans. In this work, we employed five typical OPFRs including tris(1,3-dichloro-2-propyl) phosphate (TDCIPP), tris(1-chloro-2-propyl) phosphate (TCIPP), tri(2-chloroethyl) phosphate (TCEP), triethyl phosphate (TEP), and 2-ethylhexyl diphenyl phosphate (EHDPHP), and performed density functional theory (DFT) calculations to clarify the CYP-catalyzed biotransformation of five OPFRs to their diester metabolites. The DFT results show that the reaction mechanism consists of Cα-hydroxylation and O-dealkylation steps, and the biotransformation activities of five OPFRs may follow the order of TCEP ≈ TEP ≈ EHDPHP > TCIPP > TDCIPP. We further performed molecular dynamics (MD) simulations to unravel the binding interactions of five OPFRs in the CYP3A4 isoform. Binding mode analyses demonstrate that CYP3A4-mediated metabolism of TDCIPP, TCIPP, TCEP, and TEP can produce the diester metabolites, while EHDPHP metabolism may generate para-hydroxyEHDPHP as the primary metabolite. Moreover, the EHDPHP and TDCIPP have higher binding potential to CYP3A4 than TCIPP, TCEP, and TEP. This work reports the biotransformation profiles and binding features of five OPFRs in CYP, which can provide meaningful clues for the further studies of the metabolic fates of OPFRs and toxicological effects associated with the relevant metabolites. Full article
(This article belongs to the Special Issue Molecular Modeling: Insights into the Enzymatic Reactions and Photochemical Processes in Biomacromolecules)
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