scholarly journals High-throughput quantum-mechanics/molecular-mechanics (ONIOM) macromolecular crystallographic refinement withPHENIX/DivCon: the impact of mixed Hamiltonian methods on ligand and protein structure

2018 ◽  
Vol 74 (11) ◽  
pp. 1063-1077 ◽  
Author(s):  
Oleg Borbulevych ◽  
Roger I. Martin ◽  
Lance M. Westerhoff
Keyword(s):  
Quantum Mechanics ◽  
Molecular Mechanics ◽  
High Throughput ◽  
Active Site ◽  
Binding Modes ◽  
Acta Cryst ◽  
Structure Based Drug Design ◽  
Energy Functionals ◽  
Conventional Methods ◽  
The Impact

Conventional macromolecular crystallographic refinement relies on often dubious stereochemical restraints, the preparation of which often requires human validation for unusual species, and on rudimentary energy functionals that are devoid of nonbonding effects owing to electrostatics, polarization, charge transfer or even hydrogen bonding. While this approach has served the crystallographic community for decades, as structure-based drug design/discovery (SBDD) has grown in prominence it has become clear that these conventional methods are less rigorous than they need to be in order to produce properly predictive protein–ligand models, and that the human intervention that is required to successfully treat ligands and other unusual chemistries found in SBDD often precludes high-throughput, automated refinement. Recently, plugins to thePython-based Hierarchical ENvironment for Integrated Xtallography(PHENIX) crystallographic platform have been developed to augment conventional methods with thein situuse of quantum mechanics (QM) applied to ligand(s) along with the surrounding active site(s) at each step of refinement [Borbulevychet al.(2014),Acta CrystD70, 1233–1247]. This method (Region-QM) significantly increases the accuracy of the X-ray refinement process, and this approach is now used, coupled with experimental density, to accurately determine protonation states, binding modes, ring-flip states, water positions and so on. In the present work, this approach is expanded to include a more rigorous treatment of the entire structure, including the ligand(s), the associated active site(s) and the entire protein, using a fully automated, mixed quantum-mechanics/molecular-mechanics (QM/MM) Hamiltonian recently implemented in theDivConpackage. This approach was validated through the automatic treatment of a population of 80 protein–ligand structures chosen from the Astex Diverse Set. Across the entire population, this method results in an average 3.5-fold reduction in ligand strain and a 4.5-fold improvement inMolProbityclashscore, as well as improvements in Ramachandran and rotamer outlier analyses. Overall, these results demonstrate that the use of a structure-wide QM/MM Hamiltonian exhibits improvements in the local structural chemistry of the ligand similar to Region-QM refinement but with significant improvements in the overall structure beyond the active site.

Hybrid Quantum Mechanics/Molecular Mechanics (QM/MM) Simulation: A Tool for Structure-based Drug Design and Discovery

2021 ◽  
Vol 21 ◽  
Author(s):  
Prajakta U. Kulkarni ◽  
Harshil Shah ◽  
Vivek K. Vyas
Keyword(s):  
Quantum Mechanics ◽  
Drug Design ◽  
Molecular Mechanics ◽  
Chemical Reactions ◽  
Classical Mechanics ◽  
Molecular Structures ◽  
Protein Crystal ◽  
Structure Based Drug Design ◽  
Structure And Property ◽  
Qsar Models

: Quantum mechanics (QM) is physics based theory which explains the physical properties of nature at the level of atoms and sub-atoms. Molecular mechanics (MM) construct molecular systems through the use of classical mechanics. So, hybrid quantum mechanics and molecular mechanics (QM/MM) when combined together can act as computer-based methods which can be used to calculate structure and property data of molecular structures. Hybrid QM/MM combines the strengths of QM with accuracy and MM with speed. QM/MM simulation can also be applied for the study of chemical process in solutions as well as in the proteins, and has a great scope in structure-based drug design (CADD) and discovery. Hybrid QM/MM also applied to HTS, to derive QSAR models and due to availability of many protein crystal structures; it has a great role in computational chemistry, especially in structure- and fragment-based drug design. Fused QM/MM simulations have been developed as a widespread method to explore chemical reactions in condensed phases. In QM/MM simulations, the quantum chemistry theory is used to treat the space in which the chemical reactions occur; however the rest is defined through molecular mechanics force field (MMFF). In this review, we have extensively reviewed recent literature pertaining to the use and applications of hybrid QM/MM simulations for ligand and structure-based computational methods for the design and discovery of therapeutic agents.

The reaction mechanism of retaining glycosyltransferases

2016 ◽  
Vol 44 (1) ◽  
pp. 51-60 ◽  
Author(s):  
Albert Ardèvol ◽  
Javier Iglesias-Fernández ◽  
Víctor Rojas-Cervellera ◽  
Carme Rovira
Keyword(s):  
Quantum Mechanics ◽  
Reaction Mechanism ◽  
Molecular Mechanics ◽  
Active Site ◽  
Molecular Mechanisms ◽  
Catalytic Mechanism ◽  
Strong Support ◽  
Front Face ◽  
Displacement Reaction ◽  
Displacement Mechanism

The catalytic mechanism of retaining glycosyltransferases (ret-GTs) remains a controversial issue in glycobiology. By analogy to the well-established mechanism of retaining glycosidases, it was first suggested that ret-GTs follow a double-displacement mechanism. However, only family 6 GTs exhibit a putative nucleophile protein residue properly located in the active site to participate in catalysis, prompting some authors to suggest an unusual single-displacement mechanism [named as front-face or SNi (substitution nucleophilic internal)-like]. This mechanism has now received strong support, from both experiment and theory, for several GT families except family 6, for which a double-displacement reaction is predicted. In the last few years, we have uncovered the molecular mechanisms of several retaining GTs by means of quantum mechanics/molecular mechanics (QM/MM) metadynamics simulations, which we overview in the present work.

scholarly journals Bioengineering of Cytochrome P450 OleTJE: How Does Substrate Positioning Affect the Product Distributions?

Molecules ◽  
2020 ◽  
Vol 25 (11) ◽  
pp. 2675 ◽  
Author(s):  
Fabián G. Cantú Reinhard ◽  
Yen-Ting Lin ◽  
Agnieszka Stańczak ◽  
Sam P. de Visser
Keyword(s):  
Quantum Mechanics ◽  
Molecular Mechanics ◽  
Active Site ◽  
Density Functional ◽  
Computational Study ◽  
Cation Radical ◽  
Wild Type ◽  
Compound I ◽  
Substrate Activation ◽  
Product Distributions

The cytochromes P450 are versatile enzymes found in all forms of life. Most P450s use dioxygen on a heme center to activate substrates, but one class of P450s utilizes hydrogen peroxide instead. Within the class of P450 peroxygenases, the P450 OleTJE isozyme binds fatty acid substrates and converts them into a range of products through the α-hydroxylation, β-hydroxylation and decarboxylation of the substrate. The latter produces hydrocarbon products and hence can be used as biofuels. The origin of these product distributions is unclear, and, as such, we decided to investigate substrate positioning in the active site and find out what the effect is on the chemoselectivity of the reaction. In this work we present a detailed computational study on the wild-type and engineered structures of P450 OleTJE using a combination of density functional theory and quantum mechanics/molecular mechanics methods. We initially explore the wild-type structure with a variety of methods and models and show that various substrate activation transition states are close in energy and hence small perturbations as through the protein may affect product distributions. We then engineered the protein by generating an in silico model of the double mutant Asn242Arg/Arg245Asn that moves the position of an active site Arg residue in the substrate-binding pocket that is known to form a salt-bridge with the substrate. The substrate activation by the iron(IV)-oxo heme cation radical species (Compound I) was again studied using quantum mechanics/molecular mechanics (QM/MM) methods. Dramatic differences in reactivity patterns, barrier heights and structure are seen, which shows the importance of correct substrate positioning in the protein and the effect of the second-coordination sphere on the selectivity and activity of enzymes.

scholarly journals Combined quantum mechanics/molecular mechanics (QM/MM) methods to understand the charge density distribution of estrogens in the active site of estrogen receptors

RSC Advances ◽  
2019 ◽  
Vol 9 (69) ◽  
pp. 40758-40771 ◽  
Author(s):  
C. Kalaiarasi ◽  
S. Manjula ◽  
P. Kumaradhas
Keyword(s):  
Quantum Mechanics ◽  
Molecular Recognition ◽  
Ligand Binding ◽  
Density Distribution ◽  
Charge Density ◽  
Estrogen Receptors ◽  
Molecular Mechanics ◽  
Active Site ◽  
Charge Density Distribution

The ligand binding to protein and host–guest interactions are ubiquitous for molecular recognition.

scholarly journals On the Catalytic Activity of the Engineered Coiled-Coil Heptamer Mimicking the Hydrolase Enzymes: Insights from a Computational Study

2020 ◽  
Vol 21 (12) ◽  
pp. 4551
Author(s):  
Mario Prejanò ◽  
Isabella Romeo ◽  
Nino Russo ◽  
Tiziana Marino
Keyword(s):  
Molecular Dynamics ◽  
Quantum Mechanics ◽  
Catalytic Activity ◽  
Molecular Mechanics ◽  
Active Site ◽  
Esterase Activity ◽  
De Novo ◽  
Computational Study ◽  
Catalytic Triad ◽  
Molecular Mechanics Calculations

Recently major advances were gained on the designed proteins aimed to generate biomolecular mimics of proteases. Although such enzyme-like catalysts must still suffer refinements for improving the catalytic activity, at the moment, they represent a good example of artificial enzymes to be tested in different fields. Herein, a de novo designed homo-heptameric peptide assembly (CC-Hept) where the esterase activity towards p-nitro-phenylacetate was obtained for introduction of the catalytic triad (Cys-His-Glu) into the hydrophobic matrix, is the object of the present combined molecular dynamics and quantum mechanics/molecular mechanics investigation. Constant pH Molecular Dynamics simulations on the apoform of CC-Hept suggested that the Cys residues are present in the protonated form. Molecular dynamics (MD) simulations of the enzyme–substrate complex evidenced the attitude of the enzyme-like system to retain water molecules, necessary in the hydrolytic reaction, in correspondence of the active site, represented by the Cys-His-Glu triad on each of the seven chains, without significant structural perturbations. A detailed reaction mechanism of esterase activity of CC-Hept-Cys-His-Glu was investigated on the basis of the quantum mechanics/molecular mechanics calculations employing a large quantum mechanical (QM) region of the active site. The proposed mechanism is consistent with available esterases kinetics and structural data. The roles of the active site residues were also evaluated. The deacylation phase emerged as the rate-determining step, in agreement with esterase activity of other natural proteases.

On-the-Fly Determination of Active Region Centers in Adaptive-Partitioning QM/MM

2020 ◽  
Author(s):  
Zenghui Yang
Keyword(s):  
Quantum Mechanics ◽  
Active Region ◽  
Molecular Mechanics ◽  
Active Regions ◽  
Available Energy ◽  
Adaptive Partitioning ◽  
Different Levels

Quantum mechanics/molecular mechanics (QM/MM) methods partition the system into active and environmental regions and treat them with different levels of theory, achieving accuracy and efficiency at the same time. Adaptive-partitioning (AP) QM/MM methods allow on-the-fly changes to the QM/MM partitioning of the system. Many of the available energy-based AP-QM/MM methods partition the system according to distances to pre-chosen centers of active regions. For such AP-QM/MM methods, I develop an adaptive-center (AC) method that allows on-the-fly determination of the centers of active regions according to general geometrical or potential-related criteria, extending the range of application of energy-based AP-QM/MM methods to systems where active regions may occur or vanish during the simulation.

A Conserved Asparagine in a Ubiquitin Conjugating Enzyme Positions the Substrate for Nucleophilic Attack

2018 ◽  
Author(s):  
Walker M. Jones ◽  
Aaron G. Davis ◽  
R. Hunter Wilson ◽  
Katherine L. Elliott ◽  
Isaiah Sumner
Keyword(s):  
Molecular Dynamics ◽  
Quantum Mechanics ◽  
Molecular Mechanics ◽  
Reaction Rates ◽  
Nucleophilic Attack ◽  
Classical Molecular Dynamics ◽  
Ubiquitin Conjugating Enzyme ◽  
Conjugating Enzyme

We present classical molecular dynamics (MD), Born-Oppenheimer molecular dynamics (BOMD), and hybrid quantum mechanics/molecular mechanics (QM/MM) data. MD was performed using the GPU accelerated pmemd module of the AMBER14MD package. BOMD was performed using CP2K version 2.6. The reaction rates in BOMD were accelerated using the Metadynamics method. QM/MM was performed using ONIOM in the Gaussian09 suite of programs. Relevant input files for BOMD and QM/MM are available.

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