Browse
Submit Data
Databases
API
Help

Dataset Information

0 Views

0 Connections

0 Citations

0 Reanalyses

0 Downloads

Omics score: 0

Pseudobond parameters for QM/MM studies involving nucleosides, nucleotides, and their analogs.

ABSTRACT: In biological systems involving nucleosides, nucleotides, or their respective analogs, the ribose sugar moiety is the most common reaction site, for example, during DNA replication and repair. However, nucleic bases, which comprise a sizable portion of nucleotide molecules, are usually unreactive during such processes. In quantum mechanical∕molecular simulations of nucleic acid reactivity, it may therefore be advantageous to describe specific ribosyl or ribosyl phosphate groups quantum mechanically and their respective nucleic bases with a molecular mechanics potential function. Here, we have extended the pseudobond approach to enable quantum mechanical∕molecular mechanical simulations involving nucleotides, nucleosides, and their analogs in which the interface between the two subsystems is located between the sugar and the base, namely, the C(sp(3))-N(sp(2)) bond. The pseudobond parameters were optimized on a training set of 10 molecules representing several nucleotide and nucleoside bases and analogs, and they were then tested on a larger test set of 20 diverse molecules. Particular emphasis was placed on providing accurate geometries and electrostatic properties, including electrostatic potential, natural bond orbital (NBO) and atoms in molecules (AIM) charges and AIM first moments. We also tested the optimized parameters on five nucleotide and nucleoside analogues of pharmaceutical relevance and a small polypeptide (triglycine). Accuracy was maintained for these systems, which highlights the generality and transferability of the pseudobond approach.

SUBMITTER: Chaudret R

PROVIDER: S-EPMC3568090 | biostudies-other | 2013 Jan

REPOSITORIES: biostudies-other

ACCESS DATA

Json Xml

Similar Datasets

QM/MM Study of the Fosfomycin Resistance Mechanism Involving FosB Enzyme.

Project description:Multidrug-resistant organisms contain antibiotic-modifying enzymes that facilitate resistance to a variety of antimicrobial compounds. Particularly, the fosfomycin (FOF) drug can be structurally modified by several FOF-modifying enzymes before it reaches the biological target. Among them, FosB is an enzyme that utilizes l-cysteine or bacillithiol in the presence of a divalent metal to open the epoxide ring of FOF and, consequently, inactivate the drug. Here, we have used hybrid quantum mechanics/molecular mechanics (QM/MM) and molecular dynamics (MD) simulations to explore the mechanism of the reaction involving FosB and FOF. The calculated free-energy profiles show that the cost to open the epoxide ring of FOF at the C2 atom is ∼3.0 kcal/mol higher than that at the C1 atom. Besides, our QM/MM MD results revealed the critical role of conformation change of Cys9 and Asn50 to release the drug from the active site. Overall, the present study provides insights into the mechanism of FOF-resistant proteins.

| S-EPMC8154160 | biostudies-literature

Metabolism, Biochemical Actions, and Chemical Synthesis of Anticancer Nucleosides, Nucleotides, and Base Analogs.

Project description:Nucleoside, nucleotide, and base analogs have been in the clinic for decades to treat both viral pathogens and neoplasms. More than 20% of patients on anticancer chemotherapy have been treated with one or more of these analogs. This review focuses on the chemical synthesis and biology of anticancer nucleoside, nucleotide, and base analogs that are FDA-approved and in clinical development since 2000. We highlight the cellular biology and clinical biology of analogs, drug resistance mechanisms, and compound specificity towards different cancer types. Furthermore, we explore analog syntheses as well as improved and scale-up syntheses. We conclude with a discussion on what might lie ahead for medicinal chemists, biologists, and physicians as they try to improve analog efficacy through prodrug strategies and drug combinations.

| S-EPMC7717319 | biostudies-literature

QM/MM molecular dynamics studies of metal binding proteins.

Project description:Mixed quantum-classical (quantum mechanical/molecular mechanical (QM/MM)) simulations have strongly contributed to providing insights into the understanding of several structural and mechanistic aspects of biological molecules. They played a particularly important role in metal binding proteins, where the electronic effects of transition metals have to be explicitly taken into account for the correct representation of the underlying biochemical process. In this review, after a brief description of the basic concepts of the QM/MM method, we provide an overview of its capabilities using selected examples taken from our work. Specifically, we will focus on heme peroxidases, metallo-β-lactamases, α-synuclein and ligase ribozymes to show how this approach is capable of describing the catalytic and/or structural role played by transition (Fe, Zn or Cu) and main group (Mg) metals. Applications will reveal how metal ions influence the formation and reduction of high redox intermediates in catalytic cycles and enhance drug metabolism, amyloidogenic aggregate formation and nucleic acid synthesis. In turn, it will become manifest that the protein frame directs and modulates the properties and reactivity of the metal ions.

| S-EPMC4192665 | biostudies-literature

Mechanisms of Proteolytic Enzymes and Their Inhibition in QM/MM Studies.

Project description:Experimental evidence for enzymatic mechanisms is often scarce, and in many cases inadvertently biased by the employed methods. Thus, apparently contradictory model mechanisms can result in decade long discussions about the correct interpretation of data and the true theory behind it. However, often such opposing views turn out to be special cases of a more comprehensive and superior concept. Molecular dynamics (MD) and the more advanced molecular mechanical and quantum mechanical approach (QM/MM) provide a relatively consistent framework to treat enzymatic mechanisms, in particular, the activity of proteolytic enzymes. In line with this, computational chemistry based on experimental structures came up with studies on all major protease classes in recent years; examples of aspartic, metallo-, cysteine, serine, and threonine protease mechanisms are well founded on corresponding standards. In addition, experimental evidence from enzyme kinetics, structural research, and various other methods supports the described calculated mechanisms. One step beyond is the application of this information to the design of new and powerful inhibitors of disease-related enzymes, such as the HIV protease. In this overview, a few examples demonstrate the high potential of the QM/MM approach for sophisticated pharmaceutical compound design and supporting functions in the analysis of biomolecular structures.

| S-EPMC8004986 | biostudies-literature

QM/MM calculations with deMon2k.

Project description:The density functional code deMon2k employs a fitted density throughout (Auxiliary Density Functional Theory), which offers a great speed advantage without sacrificing necessary accuracy. Powerful Quantum Mechanical/Molecular Mechanical (QM/MM) approaches are reviewed. Following an overview of the basic features of deMon2k that make it efficient while retaining accuracy, three QM/MM implementations are compared and contrasted. In the first, deMon2k is interfaced with the CHARMM MM code (CHARMM-deMon2k); in the second MM is coded directly within the deMon2k software; and in the third the Chemistry in Ruby (Cuby) wrapper is used to drive the calculations. Cuby is also used in the context of constrained-DFT/MM calculations. Each of these implementations is described briefly; pros and cons are discussed and a few recent applications are described briefly. Applications include solvated ions and biomolecules, polyglutamine peptides important in polyQ neurodegenerative diseases, copper monooxygenases and ultra-rapid electron transfer in cryptochromes.

| S-EPMC6272552 | biostudies-literature

CHARMM-GUI QM/MM Interfacer for a Quantum Mechanical and Molecular Mechanical (QM/MM) Simulation Setup: 1. Semiempirical Methods.

Project description:Quantum mechanical (QM) treatments, when combined with molecular mechanical (MM) force fields, can effectively handle enzyme-catalyzed reactions without significantly increasing the computational cost. In this context, we present CHARMM-GUI QM/MM Interfacer, a web-based cyberinfrastructure designed to streamline the preparation of various QM/MM simulation inputs with ligand modification. The development of QM/MM Interfacer has been achieved through integration with existing CHARMM-GUI modules, such as PDB Reader and Manipulator, Solution Builder, and Membrane Builder. In addition, new functionalities have been developed to facilitate the one-stop preparation of QM/MM systems and enable interactive and intuitive ligand modifications and QM atom selections. QM/MM Interfacer offers support for a range of semiempirical QM methods, including AM1(+/d), PM3(+/PDDG), MNDO(+/d, +/PDDG), PM6, RM1, and SCC-DFTB, tailored for both AMBER and CHARMM. A nontrivial setup related to ligand modification, link-atom insertion, and charge distribution is automatized through intuitive user interfaces. To illustrate the robustness of QM/MM Interfacer, we conducted QM/MM simulations of three enzyme-substrate systems: dihydrofolate reductase, insulin receptor kinase, and oligosaccharyltransferase. In addition, we have created three tutorial videos about building these systems, which can be found at https://www.charmm-gui.org/demo/qmi. QM/MM Interfacer is expected to be a valuable and accessible web-based tool that simplifies and accelerates the setup process for hybrid QM/MM simulations.

| S-EPMC11209942 | biostudies-literature

Purines 2010: Adenine Nucleosides and Nucleotides in Biomedicine

Project description: Not available

| S-EPMC2908743 | biostudies-literature

Systematic analysis of enzymatic DNA polymerization using oligo-DNA templates and triphosphate analogs involving 2',4'-bridged nucleosides.

Project description:In order to systematically analyze the effects of nucleoside modification of sugar moieties in DNA polymerase reactions, we synthesized 16 modified templates containing 2',4'-bridged nucleotides and three types of 2',4'-bridged nucleoside-5'-triphospates with different bridging structures. Among the five types of thermostable DNA polymerases used, Taq, Phusion HF, Vent(exo-), KOD Dash and KOD(exo-), the KOD Dash and KOD(exo-) DNA polymerases could smoothly read through the modified templates containing 2'-O,4'-C-methylene-linked nucleotides at intervals of a few nucleotides, even at standard enzyme concentrations for 5 min. Although the Vent(exo-) DNA polymerase also read through these modified templates, kinetic study indicates that the KOD(exo-) DNA polymerase was found to be far superior to the Vent(exo-) DNA polymerase in accurate incorporation of nucleotides. When either of the DNA polymerase was used, the presence of 2',4'-bridged nucleotides on a template strand substantially decreased the reaction rates of nucleotide incorporations. The modified templates containing sequences of seven successive 2',4'-bridged nucleotides could not be completely transcribed by any of the DNA polymerases used; yields of longer elongated products decreased in the order of steric bulkiness of the modified sugars. Successive incorporation of 2',4'-bridged nucleotides into extending strands using 2',4'-bridged nucleoside-5'-triphospates was much more difficult. These data indicate that the sugar modification would have a greater effect on the polymerase reaction when it is adjacent to the elongation terminus than when it is on the template as well, as in base modification.

| S-EPMC2490744 | biostudies-literature

Comparative Computational Approach To Study Enzyme Reactions Using QM and QM-MM Methods.

Project description:Choline oxidase catalyzes oxidation of choline into glycine betaine through a two-step reaction pathway employing flavin as the cofactor. On the light of kinetic studies, it is proposed that a hydride ion is transferred from α-carbon of choline/hydrated-betaine aldehyde to the N5 position of flavin in the rate-determining step, which is preceded by deprotonation of hydroxyl group of choline/hydrated-betaine aldehyde to one of the possible basic side chains. Using the crystal structure of glycine betaine-choline oxidase complex, we formulated two computational systems to study the hydride-transfer mechanism including main active-site amino acid side chains, flavin cofactor, and choline as a model system. The first system used pure density functional theory calculations, whereas the second approach used a hybrid ONIOM approach consisting of density functional and molecular mechanics calculations. We were able to formulate in silico model active sites to study the hydride-transfer steps by utilizing noncovalent chemical interactions between choline/betaine aldehyde and active-site amino acid chains using an atomistic approach. We evaluated and compared the geometries and energetics of hydride-transfer process using two different systems. We highlighted chemical interactions and studied the effect of protonation state of an active-site histidine base on the energetics of transfer. Furthermore, we evaluated energetics of the second hydride-transfer process as well as hydration of betaine aldehyde.

| S-EPMC6643517 | biostudies-literature

QM/MM studies of hairpin ribozyme self-cleavage suggest the feasibility of multiple competing reaction mechanisms.

Project description:The hairpin ribozyme is a prominent member of small ribozymes since it does not require metal ions to achieve catalysis. Guanine 8 (G8) and adenine 38 (A38) have been identified as key participants in self-cleavage and -ligation. We have carried out hybrid quantum-mechanical/molecular mechanical (QM/MM) calculations to evaluate the energy along several putative reaction pathways. The error of our DFT description of the QM region was tested and shown to be ~1 kcal/mol. We find that self-cleavage of the hairpin ribozyme may follow several competing microscopic reaction mechanisms, all with calculated activation barriers in good agreement with those from experiment (20-21 kcal/mol). The initial nucleophilic attack of the A-1(2'-OH) group on the scissile phosphate is predicted to be rate-limiting in all these mechanisms. An unprotonated G8(-) (together with A38H(+)) yields a feasible activation barrier (20.4 kcal/mol). Proton transfer to a nonbridging phosphate oxygen also leads to feasible reaction pathways. Finally, our calculations consider thio-substitutions of one or both nonbridging oxygens of the scissile phosphate and predict that they have only a negligible effect on the reaction barrier, as observed experimentally.

| S-EPMC3223549 | biostudies-literature

OmicsDI is part of the ELIXIR infrastructure

OmicsDI is an Elixir interoperability service. Learn more ›

Tweets

OmicsDI Databases

PRIDE
PeptideAtlas
MassIVE
JPOST Repository
Physiome Model Repository

EGA
EVA
ENA
LINCS
PAXDB
Cell Collective

MetaboLights
Metabolomics Workbench
MetabolomeExpress
GNPS
BioModels
FAIRDOMHub

ArrayExpress
dbGaP
ExpressionAtlas
GEO
NODE

Information

Databases
Help
API
Contact us
Code on GitHub
Terms of use
Submit Data