scholarly journals Chelator-based parameterization of the 12-6-4LJ molecular mechanics potential for more realistic metal ion-protein interactions

2021 ◽  
Author(s):  
Paulius Kantakevičius ◽  
Calvin Mathiah ◽  
Linus Johannissen ◽  
Sam Hay
Keyword(s):  
Molecular Mechanics ◽  
Protein Interactions ◽  
Metal Ion ◽  
Binding Energies ◽  
Coordination Numbers ◽  
Biochemical Processes ◽  
Wide Range ◽  
Experimental Values ◽  
Dynamics Simulations ◽  
Metal Ion Interactions

Metal ions are associated with a variety of proteins and play critical roles in a wide range of biochemical processes. There are multiple ways to study and quantify protein-metal ion interactions, including by molecular dynamics simulations. Recently, the Amber molecular mechanics forcefield was modified to include a 12-6-4LJ potential, which allows better description of non-bonded terms through the additional pairwise Cij coefficients. Here, we demonstrate a method of generating Cij parameters that allows parametrization of specific metal ion-ligating groups in order to tune binding energies computed by thermodynamic integration. The new Cij coefficients were tested on a series of chelators: EDTA, NTA, EGTA and the EF1 loop peptides from the proteins lanmodulin and calmodulin. The new parameters show significant improvements in computed binding energies relative to existing force fields and produce coordination numbers and ion-oxygen distances that are in good agreement with experimental values. This parametrization method should be extensible to a range of other systems and could be readily adapted to tune properties other than binding energies.

scholarly journals Performance Assessment of a Planing Hull Using the Smoothed Particle Hydrodynamics Method

2021 ◽  
Vol 9 (3) ◽  
pp. 244 ◽  
Author(s):  
Bonaventura Tagliafierro ◽  
Simone Mancini ◽  
Pablo Ropero-Giralda ◽  
José M. Domínguez ◽  
Alejandro J. C. Crespo ◽  
...  
Keyword(s):  
Smoothed Particle Hydrodynamics ◽  
Turbulence Models ◽  
Finite Volume Methods ◽  
Wide Range ◽  
Particle Hydrodynamics ◽  
Smoothed Particle ◽  
Smoothed Particle Hydrodynamics Method ◽  
Experimental Values ◽  
Dynamics Simulations ◽  
Mesh Less

Computational Fluid Dynamics simulations of planing hulls are generally considered less reliable than simulations of displacement hulls. This is due to the flow complexity around planing hulls, especially in the bow region, where the sprays are formed. The recent and constant increasing of computational capabilities allows simulating planing hull features, with more accurate turbulence models and advanced meshing procedures. However, mesh-based approaches based on the finite volume methods have shown to be limited in capturing all the phenomena around a planing hull. As such, the focus of this study is on evaluating the ability of the Smoothed Particle Hydrodynamics mesh-less method to numerically solve the 3-D flow around a planing hull and simulate more accurately the spray structures, which is a rather challenging task to be performed with mesh-based tools. A novel application of the DualSPHysics code for simulating a planing hull resistance test has been proposed and applied to the parent hull of the Naples warped planing hull Systematic Series. The drag and the running attitudes (heave and dynamic trim angle) are computed for a wide range of Froude’s numbers and discussed concerning experimental values.

scholarly journals High-Throughput Molecular Dynamics Simulations and Validation of Thermophysical Properties of Polymers

2020 ◽  
Author(s):  
Mohammad Atif Faiz Afzal ◽  
Andrea Browning ◽  
Alexander Goldberg ◽  
Mathew D. Halls ◽  
Jacob L. Gavartin ◽  
...  
Keyword(s):  
Molecular Dynamics ◽  
Specific Volume ◽  
Graphics Processing Unit ◽  
Processing Unit ◽  
Molecular Systems ◽  
Branched Polyethylene ◽  
Wide Range ◽  
Experimental Values ◽  
Dynamics Simulations ◽  
Graphics Processing

Recent advances in graphics-processing-unit (GPU) hardware and improved efficiencies of atomistic simulation programs allow the screening of a large number of polymers to predict properties that require running and analyzing long Molecular Dynamics (MD) trajectories of large molecular systems. This paper outlines an efficient MD cooling simulation workflow based on GPU MD simulation and the refined Optimized Potentials for Liquids Simulation (OPLS) OPLS3e force field to calculate glass transition temperatures (T<sub>g</sub>) of 315 polymers for which experimental values were reported by Bicerano.<sup>1</sup> We observed good agreement of predicted T<sub>g</sub> values with experimental observation across a wide range of polymers, which confirms the clear utility of the described workflow. During the stepwise cooling simulation for the calculation of T<sub>g</sub>, a subset of polymers clearly showed an ordered structure developing as the temperature decreased. Such polymers have a point of discontinuity on the specific volume vs. temperature plot, which we associated with the melting temperature (T<sub>m</sub>). We demonstrate the distinction between crystallized and amorphous polymers by examining polyethylene. Linear polyethylene shows a discontinuity in the specific volume vs. temperature plot, but we do not observe the discontinuity for branched polyethylene simulations.

Metallothionein-protein interactions

2013 ◽  
Vol 4 (2) ◽  
pp. 143-160 ◽  
Author(s):  
Sílvia Atrian ◽  
Mercè Capdevila
Keyword(s):  
Protein Interactions ◽  
Stress Responses ◽  
Metal Ion ◽  
Physical Contact ◽  
Metal Exchange ◽  
Exchange Reactions ◽  
Spongiform Encephalopathies ◽  
Small Proteins ◽  
Parkinson’S Diseases ◽  
Wide Range

AbstractMetallothioneins (MTs) are a family of universal, small proteins, sharing a high cysteine content and an optimal capacity for metal ion coordination. They take part in a plethora of metal ion-related events (from detoxification to homeostasis, storage, and delivery), in a wide range of stress responses, and in different pathological processes (tumorigenesis, neurodegeneration, and inflammation). The information on both intracellular and extracellular interactions of MTs with other proteins is here comprehensively reviewed. In mammalian kidney, MT1/MT2 interact with megalin and related receptors, and with the transporter transthyretin. Most of the mammalian MT partners identified concern interactions with central nervous system (mainly brain) proteins, both through physical contact or metal exchange reactions. Physical interactions mainly involve neuronal secretion multimers. Regarding metal swap events, brain MT3 appears to control the metal ion load in peptides whose aggregation leads to neurodegenerative disorders, such as Aβ peptide, α-synuclein, and prion proteins (Alzheimer’s and Parkinson’s diseases, and spongiform encephalopathies, respectively). Interaction with ferritin and bovine serum albumin are also documented. The intercourse of MTs with zinc-dependent enzymes and transcription factors is capable to activate/deactivate them, thus conferring MTs the role of metabolic and gene expression regulators. As some of these proteins are involved in cell cycle and proliferation control (p53, nuclear factor κB, and PKCμ), they are considered in the context of oncogenesis and tumor progression. Only one non-mammalian MT interaction, involving Drosophila MtnA and MtnB major isoforms and peroxiredoxins, has been reported. The prospective use for biomedical applications of the MT-interaction information is finally discussed.

scholarly journals Discrimination of Naturally-Occurring 2-Arylbenzofurans as Cyclooxygenase-2 Inhibitors: Insights into the Binding Mode and Enzymatic Inhibitory Activity

Biomolecules ◽  
2020 ◽  
Vol 10 (2) ◽  
pp. 176 ◽  
Author(s):  
Ericsson Coy-Barrera
Keyword(s):  
Three Dimensional ◽  
3D Qsar ◽  
Binding Mode ◽  
Binding Energies ◽  
Wide Range ◽  
Ic50 Values ◽  
Structure Relationship ◽  
Cox 2 ◽  
Dynamics Simulations

2-arylbenzofuran-containing compounds are chemical entities that can be naturally produced by several organisms. A wide-range of activities is described for several compounds of this kind and they are, therefore, valuable moieties for a lead finding from nature. Although there are in-vitro data about the activity of 2-arylbenzofuran-related compounds against cyclooxygenase (COX) enzymes, the molecular level of these COX-inhibiting constituents had not been deeply explored. Thus, 58 2-arylbenzofurans were initially screened through molecular docking within the active site of nine COX-2 crystal structures. The resulting docking scores were statistically analyzed and good reproducibility and convergence were found to discriminate the best-docked compounds. Discriminated compounds exhibited the best performance in molecular dynamics simulations as well as the most-favorable binding energies and the lowest in-vitro IC50 values for COX-2 inhibition. A three-dimensional quantitative activity-structure relationship (3D-QSAR) was also demonstrated, which showed some crucial structural requirements for enhanced enzyme inhibition. Therefore, four hits are proposed as lead structures for the development of COX-2 inhibitors based on 2-arylbenzofurans in further studies.

scholarly journals In silico discovery of SARS-CoV-2 main protease inhibitors from the carboline and quinoline database

2021 ◽  
Author(s):  
Eldar Muhtar ◽  
Mengyang Wang ◽  
Haimei Zhu
Keyword(s):  
Molecular Dynamics ◽  
Molecular Mechanics ◽  
Protease Inhibitors ◽  
Surface Area ◽  
In Silico ◽  
Binding Energies ◽  
Main Protease ◽  
Poisson Boltzmann ◽  
Dynamics Simulations ◽  
Potential Inhibitors

Aim: SARS-CoV-2 caused more than 3.8 million deaths according to the WHO. In this urgent circumstance, we aimed at screening out potential inhibitors targeting the main protease of SARS-CoV-2. Materials & methods: An in-house carboline and quinoline database including carboline, quinoline and their derivatives was established. A virtual screening in carboline and quinoline database, 50 ns molecular dynamics simulations and molecular mechanics Poisson−Boltzmann surface area calculations were carried out. Results: The top 12 molecules were screened out preliminarily. The molecular mechanics Poisson−Boltzmann surface area ranking showed that p59_7m, p12_7e, p59_7k stood out with the lowest binding energies of -24.20, -17.98, -17.67 kcal/mol, respectively. Conclusion: The study provides powerful in silico results that indicate the selected molecules are valuable for further evaluation as SARS-CoV-2 main protease inhibitors.

scholarly journals A metal-dependent switch moderates activity of the hexameric M17 aminopeptidases

2018 ◽  
Author(s):  
Nyssa Drinkwater ◽  
Wei Yang ◽  
Blake T. Riley ◽  
Brooke K. Hayes ◽  
Komagal Kannan Sivaraman ◽  
...  
Keyword(s):  
Metal Ion ◽  
Active Sites ◽  
Binding Pocket ◽  
Metal Center ◽  
Processing Enzymes ◽  
Novel Structure ◽  
Wide Range ◽  
Binuclear Metal ◽  
Biochemical Analyses ◽  
Dynamics Simulations

AbstractThe metal-dependent M17 aminopeptidases are conserved throughout all kingdoms of life. The large enzyme family is characterised by a conserved binuclear metal center and a distinctive homohexameric arrangement. To understand the mechanistic role of the hexameric assembly, we undertook an investigation of the structure and dynamics of the M17 aminopeptidase from P. falciparum, PfA-M17. We describe a novel structure of PfA-M17, which shows that the active sites of each trimer are linked by a dynamic loop, and that the loop movement is coupled with a drastic rearrangement of the binuclear metal center and substrate-binding pocket. Molecular dynamics simulations, supported by biochemical analyses of PfA-M17 variants, demonstrate that this rearrangement is inherent to PfA-M17, and that the transition between the active and inactive states is part of a dynamic regulatory mechanism. Key to the mechanism is a re-modelling of the binuclear metal center, which occurs in response to a signal from the neighbouring active site, and serves to moderate the rate of proteolysis under different environmental conditions. Therefore, this work has identified the precise mechanism by which oligomerization contributes to PfA-M17 function. Further, it has described a novel role for metal cofactors in the regulation of enzymes with implications for the wide range of metalloenzymes that operate via a two-metal ion catalytic center including DNA processing enzymes and metalloproteases.

scholarly journals High-Throughput Molecular Dynamics Simulations and Validation of Thermophysical Properties of Polymers

2020 ◽  
Author(s):  
Mohammad Atif Faiz Afzal ◽  
Andrea Browning ◽  
Alexander Goldberg ◽  
Mathew D. Halls ◽  
Jacob L. Gavartin ◽  
...  
Keyword(s):  
Molecular Dynamics ◽  
Specific Volume ◽  
Graphics Processing Unit ◽  
Processing Unit ◽  
Molecular Systems ◽  
Branched Polyethylene ◽  
Wide Range ◽  
Experimental Values ◽  
Dynamics Simulations ◽  
Graphics Processing

Recent advances in graphics-processing-unit (GPU) hardware and improved efficiencies of atomistic simulation programs allow the screening of a large number of polymers to predict properties that require running and analyzing long Molecular Dynamics (MD) trajectories of large molecular systems. This paper outlines an efficient MD cooling simulation workflow based on GPU MD simulation and the refined Optimized Potentials for Liquids Simulation (OPLS) OPLS3e force field to calculate glass transition temperatures (T<sub>g</sub>) of 315 polymers for which experimental values were reported by Bicerano.<sup>1</sup> We observed good agreement of predicted T<sub>g</sub> values with experimental observation across a wide range of polymers, which confirms the clear utility of the described workflow. During the stepwise cooling simulation for the calculation of T<sub>g</sub>, a subset of polymers clearly showed an ordered structure developing as the temperature decreased. Such polymers have a point of discontinuity on the specific volume vs. temperature plot, which we associated with the melting temperature (T<sub>m</sub>). We demonstrate the distinction between crystallized and amorphous polymers by examining polyethylene. Linear polyethylene shows a discontinuity in the specific volume vs. temperature plot, but we do not observe the discontinuity for branched polyethylene simulations.

High-Throughput Molecular Dynamics Simulations and Validation of Thermophysical Properties of Polymers

2020 ◽  
Author(s):  
Mohammad Atif Faiz Afzal ◽  
Andrea Browning ◽  
Alexander Goldberg ◽  
Mathew D. Halls ◽  
Jacob L. Gavartin ◽  
...  
Keyword(s):  
Molecular Dynamics ◽  
Specific Volume ◽  
Graphics Processing Unit ◽  
Processing Unit ◽  
Molecular Systems ◽  
Branched Polyethylene ◽  
Wide Range ◽  
Experimental Values ◽  
Dynamics Simulations ◽  
Graphics Processing

Recent advances in graphics-processing-unit (GPU) hardware and improved efficiencies of atomistic simulation programs allow the screening of a large number of polymers to predict properties that require running and analyzing long Molecular Dynamics (MD) trajectories of large molecular systems. This paper outlines an efficient MD cooling simulation workflow based on GPU MD simulation and the refined Optimized Potentials for Liquids Simulation (OPLS) OPLS3e force field to calculate glass transition temperatures (T<sub>g</sub>) of 315 polymers for which experimental values were reported by Bicerano.<sup>1</sup> We observed good agreement of predicted T<sub>g</sub> values with experimental observation across a wide range of polymers, which confirms the clear utility of the described workflow. During the stepwise cooling simulation for the calculation of T<sub>g</sub>, a subset of polymers clearly showed an ordered structure developing as the temperature decreased. Such polymers have a point of discontinuity on the specific volume vs. temperature plot, which we associated with the melting temperature (T<sub>m</sub>). We demonstrate the distinction between crystallized and amorphous polymers by examining polyethylene. Linear polyethylene shows a discontinuity in the specific volume vs. temperature plot, but we do not observe the discontinuity for branched polyethylene simulations.

scholarly journals Molecular Docking and Dynamics Investigations for Identifying Potential Inhibitors of the 3-Chymotrypsin-like Protease of SARS-CoV-2: Repurposing of Approved Pyrimidonic Pharmaceuticals for COVID-19 Treatment

Molecules ◽  
2021 ◽  
Vol 26 (24) ◽  
pp. 7458
Author(s):  
Amin Osman Elzupir
Keyword(s):  
Molecular Dynamics ◽  
Molecular Docking ◽  
Molecular Mechanics ◽  
Surface Area ◽  
Active Sites ◽  
Inhibitory Effect ◽  
Binding Energies ◽  
Poisson Boltzmann ◽  
The Stability ◽  
Dynamics Simulations

This study demonstrates the inhibitory effect of 42 pyrimidonic pharmaceuticals (PPs) on the 3-chymotrypsin-like protease of SARS-CoV-2 (3CLpro) through molecular docking, molecular dynamics simulations, and free binding energies by means of molecular mechanics–Poisson Boltzmann surface area (MM-PBSA) and molecular mechanics–generalized Born surface area (MM-GBSA). Of these tested PPs, 11 drugs approved by the US Food and Drug Administration showed an excellent binding affinity to the catalytic residues of 3CLpro of His41 and Cys145: uracil mustard, cytarabine, floxuridine, trifluridine, stavudine, lamivudine, zalcitabine, telbivudine, tipiracil, citicoline, and uridine triacetate. Their percentage of residues involved in binding at the active sites ranged from 56 to 100, and their binding affinities were in the range from −4.6 ± 0.14 to −7.0 ± 0.19 kcal/mol. The molecular dynamics as determined by a 200 ns simulation run of solvated docked complexes confirmed the stability of PP conformations that bound to the catalytic dyad and the active sites of 3CLpro. The free energy of binding also demonstrates the stability of the PP–3CLpro complexes. Citicoline and uridine triacetate showed free binding energies of −25.53 and −7.07 kcal/mol, respectively. Therefore, I recommend that they be repurposed for the fight against COVID-19, following proper experimental and clinical validation.

On the Adsorption of Aspartate Derivatives to Calcite Surfaces in Aqueous Environment

2020 ◽  
Author(s):  
Robert Stepic ◽  
Lara Jurković ◽  
Ksenia Klementyeva ◽  
Marko Ukrainczyk ◽  
Matija Gredičak ◽  
...  
Keyword(s):  
Active Sites ◽  
Realistic Model ◽  
Binding Energies ◽  
Inhibition Mechanism ◽  
Aqueous Environment ◽  
Binding Modes ◽  
Carboxylate Groups ◽  
Dissolved Ions ◽  
Living Organisms ◽  
Dynamics Simulations

In many living organisms, biomolecules interact favorably with various surfaces of calcium carbonate. In this work, we have considered the interactions of aspartate (Asp) derivatives, as models of complex biomolecules, with calcite. Using kinetic growth experiments, we have investigated the inhibition of calcite growth by Asp, Asp2 and Asp3.This entailed the determination of a step-pinning growth regime as well as the evaluation of the adsorption constants and binding free energies for the three species to calcite crystals. These latter values are compared to free energy profiles obtained from fully atomistic molecular dynamics simulations. When using a flat (104) calcite surface in the models, the measured trend of binding energies is poorly reproduced. However, a more realistic model comprised of a surface with an island containing edges and corners, yields binding energies that compare very well with experiments. Surprisingly, we find that most binding modes involve the positively charged, ammonium group. Moreover, while attachment of the negatively charged carboxylate groups is also frequently observed, it is always balanced by the aqueous solvation of an equal or greater number of carboxylates. These effects are observed on all calcite features including edges and corners, the latter being associated with dominant affinities to Asp derivatives. As these features are also precisely the active sites for crystal growth, the experimental and theoretical results point strongly to a growth inhibition mechanism whereby these sites become blocked, preventing further attachment of dissolved ions and halting further growth.

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