Molecular Dynamics Simulation Technique Research Articles

Secondary structure dependence of amyloid-β(1-40) on simulation techniques and force field parameters.

Our recent studies revealed that none of the selected widely used force field parameters and molecular dynamics simulation techniques yield structural properties for the intrinsically disordered α-synuclein that are in agreement with various experiments via testing different force field parameters. Here, we extend our studies on the secondary structure properties of the disordered amyloid-β(1-40) peptide in aqueous solution. For these purposes, we conducted extensive replica exchange molecular dynamics simulations and obtained extensive molecular dynamics simulation trajectories from David E. Shaw group. Specifically, these molecular dynamics simulations were conducted using various force field parameters and obtained results are compared to our replica exchange molecular dynamics simulations and experiments. In this study, we calculated the secondary structure abundances and radius of gyration values for amyloid-β(1-40) that were simulated using varying force field parameter sets and different simulation techniques. In addition, the intrinsic disorder propensity, as well as sequence-based secondary structure predisposition of amyloid-β(1-40) and compared the findings with the results obtained from molecular simulations using various force field parameters and different simulation techniques. Our studies clearly show that the epitope region identification of amyloid-β(1-40) depends on the chosen simulation technique and chosen force field parameters. Based on comparison with experiments, we find that best computational results in agreement with experiments are obtained using the a99sb*-ildn, charmm36m, and a99sb-disp parameters for the amyloid-β(1-40) peptide in molecular dynamics simulations without parallel tempering or via replica exchange molecular dynamics simulations.

Engineering stable carbonic anhydrases for CO2 capture: a critical review.

Targeted inhibition of misregulated protein-protein interactions (PPIs) has been a promising area of investigation in drug discovery and development for human diseases. However, many constraints remain, including shallow binding surfaces and dynamic conformation changes upon interaction. A particularly challenging aspect is the undesirable off-target effects caused by inherent structural similarity among the protein families. To tackle this problem, phage display has been used to engineer PPIs for high-specificity binders with improved binding affinity and greatly reduced undesirable interactions with closely related proteins. Although general steps of phage display are standardized, library design is highly variable depending on experimental contexts. Here in this review, we examined recent advances in the structure-based combinatorial library design and the advantages and limitations of different approaches. The strategies described here can be explored for other protein-protein interactions and aid in designing new libraries or improving on previous libraries.

Trajectory Surface Hopping Approach to Condensed-Phase Nonradiative Relaxation Dynamics Using Divide-and-Conquer Spin-Flip Time-Dependent Density-Functional Tight Binding.

Nonradiative relaxation of excited molecules is central to many crucial issues in photochemistry. Condensed phases are typical contexts in which such problems are considered, and the nonradiative relaxation dynamics are expected to be significantly affected by interactions with the environment, for example, a solvent. We developed a nonadiabatic molecular dynamics simulation technique that can treat the nonradiative relaxation and explicitly include the environment in the calculations without a heavy computational burden. Specifically, we combined trajectory surface hopping with Tully's fewest-switches algorithm, a tight-binding approximated version of spin-flip time-dependent density-functional theory, and divide-and-conquer (DC) spatial fragmentation scheme. Numerical results showed that this method can treat systems with thousands of atoms within reasonable computational resources, and the error arising from DC fragmentation is negligibly small. Using this method, we obtained molecular insights into the solvent dependence of the photoexcited-state dynamics of trans-azobenzene, which demonstrate the importance of the environment for condensed-phase nonradiative relaxation.

Probing Protein-protein Interactions and Druggable Site Identification: Mechanistic Binding Events Between Ubiquitin and Zinc Finger with UFM1-specific Peptidase Domain Protein (ZUFSP).

Deubiquitinating enzymes (DUBs) protein family have been implicated in some deregulated pathways involved in carcinogeneses, such as cell cycle, gene expression, and DNA damage response (DDR). Zinc finger with UFM1-specific peptidase domain protein (ZUFSP) is one of the recently discovered members of the DUBs. To identify and cross-validate the ZUFSP binding site using the bioinformatic tools, including SiteMap&Metapocket, respectively. To understand the molecular basis of complementary ZUFSP-Ub interaction and associated structural events using MD Simulation. In this study, four binding pockets were predicted, characterized, and cross-validated based on physiochemical features such as site score, druggability score, site volume, and site size. Also, a molecular dynamics simulation technique was employed to determine the impact of ubiquitin-binding on ZUFSP. Site 1 with a site score 1.065, Size 102, D scores 1.00, and size volume 261 was predicted to be the most druggable site. Structural studies revealed that upon ubiquitin-binding, the motional movement of ZUFSP was reduced when compared to the unbound ZUFSP. Also, the ZUFSP helical arm (ZHA) domain orient in such a way that it moves closer to the Ub; this orientation enables the formation of a UBD which is very peculiar to ZUFSP. The impact of ubiquitin on ZUFSP movement and the characterization of its predicted druggable site can be targeted in the development of therapeutics.

Effect of TMAO on the Structure and Phase Transition of Lipid Membranes: Potential Role of TMAO in Stabilizing Cell Membranes under Osmotic Stress.

Extremophiles adopt strategies to deal with different environmental stresses, some of which are severely damaging to their cell membrane. To combat high osmotic stress, deep-sea organisms synthesize osmolytes, small polar organic molecules, like trimethylamine-N-oxide (TMAO), and incorporate them in the cell. TMAO is known to protect cells from high osmotic or hydrostatic pressure. Several experimental and simulation studies have revealed the roles of such osmolytes on stabilizing proteins. In contrast, the effect of osmolytes on the lipid membrane is poorly understood and broadly debated. A recent experiment has found strong evidence of the possible role of TMAO in stabilizing lipid membranes. Using the molecular dynamics (MD) simulation technique, we have demonstrated the effect of TMAO on two saturated fully hydrated lipid membranes in their fluid and gel phases. We have captured the impact of TMAO's concentration on the membrane's structural properties along with the fluid/gel phase transition temperatures. On increasing the concentration of TMAO, we see a substantial increase in the packing density of the membrane (estimated by area, thickness, and volume) and enhancement in the orientational order of lipid molecules. Having repulsive interaction with the lipid head group, the TMAO molecules are expelled away from the membrane surface, which induces dehydration of the lipid head groups, increasing the packing density. The addition of TMAO also increases the fluid/gel phase transition temperature of the membrane. All of these results are in close agreement with the experimental observations. This study, therefore, provides a molecular-level understanding of how TMAO can influence the cell membrane of deep-sea organisms and help in combating the osmotic stress condition.

Cheminformatics-Based Identification of Potential Novel Anti-SARS-CoV-2 Natural Compounds of African Origin.

The coronavirus disease 2019 (COVID-19) pandemic caused by the severe acute respiratory syndrome virus 2 (SARS-CoV-2) has impacted negatively on public health and socioeconomic status, globally. Although, there are currently no specific drugs approved, several existing drugs are being repurposed, but their successful outcomes are not guaranteed. Therefore, the search for novel therapeutics remains a priority. We screened for inhibitors of the SARS-CoV-2 main protease and the receptor-binding domain of the spike protein from an integrated library of African natural products, compounds generated from machine learning studies and antiviral drugs using AutoDock Vina. The binding mechanisms between the compounds and the proteins were characterized using LigPlot+ and molecular dynamics simulations techniques. The biological activities of the hit compounds were also predicted using a Bayesian-based approach. Six potential bioactive molecules NANPDB2245, NANPDB2403, fusidic acid, ZINC000095486008, ZINC0000556656943 and ZINC001645993538 were identified, all of which had plausible binding mechanisms with both viral receptors. Molecular dynamics simulations, including molecular mechanics Poisson-Boltzmann surface area (MM/PBSA) computations revealed stable protein-ligand complexes with all the compounds having acceptable free binding energies <−15 kJ/mol with each receptor. NANPDB2245, NANPDB2403 and ZINC000095486008 were predicted as antivirals; ZINC000095486008 as a membrane permeability inhibitor; NANPDB2403 as a cell adhesion inhibitor and RNA-directed RNA polymerase inhibitor; and NANPDB2245 as a membrane integrity antagonist. Therefore, they have the potential to inhibit viral entry and replication. These drug-like molecules were predicted to possess attractive pharmacological profiles with negligible toxicity. Novel critical residues identified for both targets could aid in a better understanding of the binding mechanisms and design of fragment-based de novo inhibitors. The compounds are proposed as worthy of further in vitro assaying and as scaffolds for the development of novel SARS-CoV-2 therapeutic molecules.

A combined experimental and computational investigation of the binary mixtures of 2-methylcyclohexanol and isobutanol

The measured densities and viscosities of the binary mixtures of the isobutanol and 2-methylcyclohexanol were reported experimentally in a certain range of concentrations at temperatures 293.15 to 313.15 K and at atmospheric pressure. From the experimental results, the excess molar volumes and viscosity deviations were obtained. These values were negative and became less negative with increasing temperature. Using the density functional theory (DFT), the most stable geometric structures of isobutanol…isobutanol, isobutanol…2-methylcyclohexanol, and 2-methylcyclohexanol…2-methylcyclohexanol were analyzed. In the liquid phase, the molecular dynamics (MD) simulation technique was employed to calculate the densities, radial distribution functions (RDFs), combined distribution function (CDF), and mean square displacement (MSD) of the mixtures with certain mole fractions at 298.15 K and at 1 atm. The H-bonding interactions for these mixtures were examined by molecular dynamics simulation and quantum calculations.

Pressure-tensor method evaluation of the interfacial tension between Gay-Berne isotropic fluid and a smooth repulsive wall.

The interfacial properties of a confined thermotropic liquid crystalline material are investigated using a molecular dynamics simulation technique. The pairwise interaction among the soft ellipsoidal particles is modeled by the Gay-Berne (GB) potential. The GB ellipsoids are confined by two soft, smooth, repulsive walls defined by the Weeks-Chandler-Andersen (WCA) potential. The aperiodic confinement due to walls makes the system mechanically anisotropic. Hence using the pressure-tensor method, the interfacial tension of an interface between the bulk isotropic (I) phase and WCA wall at various number densities (ρ) is calculated. From the pressure tensor and orientational order profiles, the arrangement of ellipsoids in the bulk and the vicinity of the wall is determined. The effect of system size and the wall-particle interaction strength (εW) on is also analyzed by varying the system size and εW.

A computational approach for designing novel SARS-CoV-2 Mpro inhibitors: combined QSAR, molecular docking, and molecular dynamics simulation techniques

The promising compound T21 for treating COVID-19 at the active site of SARS-CoV-2 Mpro.

Governing parameters for pull-out of carbon nanotubes from aluminium composites: A review

The interfacial bonding between reinforcement and matrix is the key factor for the strengthening of any composite materials apart from their strengths. The enhancement in the strength of carbon nanotubes (CNT) reinforced Al composite is incommensurate rather than the extraordinary high strength of carbon nanotubes (CNTs) due to improper bonding of CNT and Al matrix at the interface. In result, the failure of CNT/Al composite has been observed due to the pull-out of CNT rather than the fracture of CNT. So, to achieve high interfacial strength, the pull-out of CNT must be characterized but due to the nano-dimension of CNT, it was found to be crucial. In recent years there are limited analytical, experimental, and molecular dynamics (MD) simulation techniques that have been developed by researchers which elucidates the interfacial strengthening of CNT/Al composites. In recent years, Chen et al. [11] fabricated the CNT-Al composite with SPS and reinforced the Al 2 O 3 at the interface of CNT and Al, which results in a fracture of CNT during pull-out and the ISS of 41 MPa was achieved. The MD simulation used to overestimate the ISS of 140.62 MPa reported by Meguid et al. [13] . In the present study, the analysis has been made to interpret most influencing fabrication techniques, characterization techniques, and parameters to characterize and enhance the interfacial strength of the CNT-Al composite from the available literature.

Molecular Dynamics Simulation Techniques as Tools in Drug Discovery and Pharmacology: A Focus on Allosteric Drugs.

Allosteric drugs are ligands that when bound to anallosteric site modify the conformational state of the pharmacological target, leading then to a modification of functional response upon binding of the endogenous ligand. Pharmacological targets are defined as biological entities, to which a ligand/drug binds and leads to a functional effect. Pharmacological targets can be proteins or nucleic acids. Computational approaches such as molecular dynamics (MD) sped up discovery and identification of allosteric binding sites and allosteric ligands. Classical all-atom and hybrid classical/quantum MD simulations can be generalized as simulation techniques aimed at analysis of atoms and molecular motion. Main limitations of MD simulations are related to high computational costs, that in turn limit the conformational sampling of biological systems. Indeed, other techniques have been developed to overcome limitations of MD, such as enhanced sampling MD simulations. In this chapter, classical MD and enhanced sampling MD simulations will be described, along with their application to drug discovery, with a focus on allosteric drugs.

MitImpact 3: modeling the residue interaction network of the Respiratory Chain subunits.

Numerous lines of evidence have shown that the interaction between the nuclear and mitochondrial genomes ensures the efficient functioning of the OXPHOS complexes, with substantial implications in bioenergetics, adaptation, and disease. Their interaction is a fascinating and complex trait of the eukaryotic cell that MitImpact explores with its third major release. MitImpact expands its collection of genomic, clinical, and functional annotations of all non-synonymous substitutions of the human mitochondrial genome with new information on putative Compensated Pathogenic Deviations and co-varying amino acid sites of the Respiratory Chain subunits. It further provides evidence of energetic and structural residue compensation by techniques of molecular dynamics simulation. MitImpact is freely accessible at http://mitimpact.css-mendel.it.

Surface morphological and quantum chemical studies of some expired drug molecules as potential corrosion inhibitors for mild steel in chloride medium

Three anti-diabetic drug based biomolecules (Acarbose, Voglibose and Miglitol) were investigated for their corrosion inhibitive effect on mild steel in 700 ppm NaCl solution. Corrosion tests were conducted using weight loss measurements, electrochemical measurements, surface morphologies, quantum chemical studies and molecular dynamics simulation techniques. The results showed increasing corrosion inhibition efficiency with increasing concentrations of all studied biomolecules. The addition of Zn ion (synergistic effect) increased the inhibition of Acarbose, Voglibose and Miglitol on mild steel to a considerable extent. The anodic mode of inhibition mechanism was proposed for the effect of examined inhibitors, as revealed by Tafel polarization technique. Adsorption process of all the investigated inhibitors on the mild steel surface obeys the Langmuir adsorption isotherm. The surface morphologies of the mild steel were studied using SEM and EDXA. The experimental results are well correlate with the quantum chemical and molecular dynamics simulation results. The trend of corrosion protection efficiency of the drug based biomolecule is Ac > Vo > Mi as observed from experimental, theoretical and simulation studies.

Anions of Ionic Liquids Are Important Players in the Rescue of DNA Damage.

The non-targeted action of fungicides generates genotoxic effect in vertebrates by perturbing the structure of DNA, which impacts its replication and transcriptional process, leading to several serious gene associated diseases. Hence, finding a suitable medium that can reduce/reverse the structural perturbation of DNA induced by fungicide, viz. dodine, is essential. Spectroscopic as well as molecular dynamics simulation techniques have been implemented to understand the effect of ionic liquids (ILs) having a tetramethylguanidinium cation along with short and long hydrophobic chain anions mixed with fungicide. The addition of ILs possessing anions with long hydrophobic chain blocks the fungicide from binding in the groove region of DNA by forming micelle-like structure and reverses the structural change induced by the fungicide. The hydrophobicity of long hydrocarbon and fluorocarbon chains of anions is a key parameter for reversing the effect of fungicide as small anion based ILs are incapable of annulling the structural change of DNA.

A combined experimental, geometry optimization and molecular dynamic simulations study of the binary mixtures of cis and trans 2-methylcyclohexanol and aniline

The interactions between the molecules of 2-methylcyclohexanol and aniline were studied from the experimental and computational view. From the experimental, densities of binary mixtures of 2-methylcyclohexanol with aniline have been measured for the assignable mole fractions at 293.15, 298.15, 303.15, 308.15 and 313.15 K and at absolute pressure of 86.8 kPa. From this data, excess molar volumes have been calculated. Due to the deviation from the ideal state of the mixtures, excess molar volumes were negative for 2-methylcyclohexanol + aniline systems. The most stable geometric structures of 2-methylcyclohexanol … 2-methylcyclohexanol, 2-methylcyclohexanol … aniline and aniline… aniline have been investigated in the gas phase by the density functional theory (DFT). In the liquid phase, the molecular dynamics (MD) simulation technique was employed to determine the densities, radial distribution functions (RDFs) and mean square displacement (MSD) of the systems with different mole fractions at 298.15 K and at 1 atm. By the combination of experimental, molecular dynamics simulation and quantum calculations, a suitable microscopic view of the structures of these liquids and the important hydrogen bonding sites were presented.

Multi-spectroscopic investigation, molecular docking and molecular dynamic simulation of competitive interactions between flavonoids (quercetin and rutin) and sorafenib for binding to human serum albumin

The main mechanism for drug-drug interaction is displacement reaction of ligands from their protein binding sites. The aim of this study was to evaluate anticancer drug sorafenib displacement from the binding site on human serum albumin by commonly used plant flavonoids quercetin and rutin. The interaction between bio-macromolecules and drugs can also cause changes in protein structure and therefore was evaluated in this study by spectroscopic and molecular dynamic simulation techniques. Serum albumin, the main protein in the plasma acts in the disposition of many drugs and therefore, is a model protein for investigating drug/ligand binding and alteration in the spectrophotometric and molecular docking properties of drug/ligand. All the studied ligands sorafenib, quercetin and rutin bind to HSA with different binding affinity. The displacement of ligands from their binding sites was inferred from comparison of quenching and binding constants of binary and ternary systems. Conformational changes in the HSA were found with UV-spectroscopic, circular dichroism, FT-IR and three dimensional studies. The molecular dynamic simulation studies suggest a stable complex formation between HSA and sorafenib. Binding studies for HSA-sorafenib in presence of quercetin and rutin indicated displacement of sorafenib from its binding site.

Atomic Ordering at the Liquid-Al/MgAl2O4 Interfaces from Ab Initio Molecular Dynamics Simulations

MgAl2O4 spinel particles exist inevitably in Al-Mg alloy melts and may act as potential substrates for heterogeneous nucleation of solid aluminum during solidification processing. In this paper, we investigated systematically the atomic ordering of liquid Al adjacent to liquid-Al/MgAl2O4{1 1 1} interfaces using an ab initio molecular dynamics simulation technique. Our simulations revealed that the interaction between the liquid metal and the spinel surface results in the formation of an ordered metal layer that terminates the substrate. This new terminating layer is positively charged, chemically bonded to the substrate, topologically rough, and structurally coupled with the metal sublayers beneath the outmost oxygen layer. The present results may shed new light on the role of spinel particles in Al-Mg alloys and on heterogeneous nucleation processes in general.

Controlling the Chain Folding for the Synthesis of Single-Chain Polymer Nanoparticles Using Thermoresponsive Polymers

Synthetic polymer single-chain nanoparticles (SCNPs) are an emerging new class of nanomaterials that possess similar folded structures as natural proteins. However, most SCNPs reported so far are p...

Lateral and flexural thermal transport in stanene/2D-SiC van der Waals heterostructure

Thermal management is one of the key challenges in nanoelectronic and optoelectronic devices. The development of a van der Waals heterostructure (vdWH) using the vertical positioning of different two-dimensional (2D) materials has recently appeared as a promising way of attaining desirable electrical, optical, and thermal properties. Here, we explore the lateral and flexural thermal conductivity of stanene/2D-SiC vdWH utilizing the reverse non-equilibrium molecular dynamics simulation and transient pump-probe technique. The effects of length, area, coupling strength and temperature on the thermal transport are studied systematically. The projected lateral thermal conductivity of a stanene/2D-SiC hetero-bilayer is found to be 66.67 , which is greater than stanene, silicene, germanene, MoSe2 and even higher than some hetero-bilayers, including MoS2/MoSe2 and stanene/silicene. The lateral thermal conductivity increases as the length increases, while it tends to decrease with increasing temperature. The computed flexural interfacial thermal resistance between stanene and 2D-SiC is 3.0622 K.m2 W−1, which is close to other 2D hetero-bilayers. The interfacial resistance between stanene and 2D-SiC is reduced by 70.49% and 50.118% as the temperature increases from 100 K to 600 K and the coupling factor increases from to , respectively. In addition, various phonon modes are evaluated to disclose the fundamental mechanisms of thermal transport in the lateral and flexural direction of the hetero-bilayer. These results are important in order to understand the heat transport phenomena of stanene/2D-SiC vdWH, which could be useful for enhancing their promising applications.

Abnormal orderly transformation in supercooled state of an Al-based alloy

To understand the underlying mechanism behind the precipitation of high-density face-centered cubic Al nanoparticles during the annealing or preparation of Al-based metallic glass, we used molecular dynamics simulation technique to study the atomic structure evolution of Al-rich and Al-depleted melts in the Al-Zr binary system under rapid cooling conditions. From the quantitative characterization of thermodynamic properties, kinetic properties, and atomic structure, we found that an abnormal orderly transformation occurs in the supercooled liquid of Al-rich alloy, which includes two basic stages, namely, directional diffusion and stabilization of defect clusters. The thermodynamic essence of this transformation is to reduce the Gibbs free energy of the entire system by improve the cluster packing efficiency of atomic structure, preventing the supercooled liquid from being in an unstable state. An important consequence of the abnormal orderly transformation is the formation of nanoscale Al-rich regions in the supercooled liquid. These regions can readily promote the precipitation of high-density face-centered cubic Al nanoparticles, thereby reducing the complete amorphization ability of Al-based alloy melt.