Molecular docking and dynamic simulations of benzimidazoles with beta-tubulins

It is of interest to document the molecular docking and dynamic simulations of benzimidazoles with beta-tubulins in the context of anthelmintic activity. We document the compound BI-02 (2-(3,4-dimethyl phenyl)-1H-1,3-benzimidazole (BI-02) with optimal bindig features compared to the standard molecule albendazole (7.0 Kcal/mol) with binding energy -8.50 Kcal/mol and _PIC₅₀ value 583.62 nM.     

Molecular dynamics simulations of interaction between sub-bituminous coal and water

The high moisture content of sub-bituminous coal is associated with the interactions between coal and water. Because of complex composition and structure, the graphite surface modified by hydroxyl, carboxyl and carbonyl groups was used to represent the surface model of sub-bituminous coal according to XPS results. Density profiles for oxygen atoms and hydrogen atoms indicate that the coal surface properties affect the structural and dynamic characteristics of the interfacial water molecules. The interfacial water exhibits much more ordering than bulk water. The results of radial distribution functions, mean square displacement and local self-diffusion coefficient for water molecule related to three oxygen moieties confirmed that the water molecules prefer to absorb with carboxylic groups, and adsorption of water molecules at the hydroxy and carbonyl is similar.     

Molecular dynamics simulations of Leu-enkephalin in water and DMSO.

The structure of Leu-enkephalin (L-Enk) and Met-enkephalin (M-Enk) have frequently been studied, in particular by nuclear magnetic resonance spectroscopy. After more than 20 years of research, it was concluded that enkephalins have no preferred structure in aqueous solution, but that they may have in other solvents. We have performed molecular dynamics simulations of zwitterionic L-Enk in water, and zwitterionic as well as neutral L-Enk dimethyl sulfoxide (DMSO). In water the peptide is very flexible, although there seems to be a preference for compact conformations. In DMSO, the peptide forms a clear salt bridge in the zwitterionic form, but has no preferred conformation in the neutral form. This difference in conformation may provide an explanation for measurements in DMSO in which multiple conformations were found to exist. In this paper we introduce a new formulation for a dihedral angle autocorrelation function, and apply it to study side-chain dynamics in L-Enk. We find that the side-chain dynamics of the large Tyr and Phe residues cannot be adequately sampled in 2.0-ns simulations, while this does seem to be possible for the smaller Leu side chain.     

Molecular dynamic simulations and structure-based pharmacophore development for farnesyltransferase inhibitors discovery

Farnesyltransferase is one of the enzyme targets for the development of drugs for diseases, including cancer, malaria, progeria, etc. In the present study, the structure-based pharmacophore models have been developed from five complex structures (1LD7, 1NI1, 2IEJ, 2ZIR and 2ZIS) obtained from the protein data bank. Initially, molecular dynamic (MD) simulations were performed for the complexes for 10?ns using AMBER 12 software. The conformers of the complexes (75) generated from the equilibrated protein were undergone protein–ligand interaction fingerprint (PLIF) analysis. The results showed that some important residues, such as LeuB96, TrpB102, TrpB106, ArgB202, TyrB300, AspB359 and TyrB361, are predominantly present in most of the complexes for interactions. These residues form side chain acceptor and surface (hydrophobic or π–π) kind of interactions with the ligands present in the complexes. The structure-based pharmacophore models were generated from the fingerprint bits obtained from PLIF analysis. The pharmacophore models have 3–4 pharmacophore contours consist of acceptor and metal ligation (Acc & ML), hydrophobic (HydA) and extended acceptor (Acc2) features with the radius ranging between 1–3?Å for Acc & ML and 1–2?Å for HydA. The excluded volumes of the pharmacophore contours radius are between 1–2?Å. Further, the distance between the interacting groups, root mean square deviation (RMSD), root mean square fluctuation (RMSF) and radial distribution function (RDF) analysis were performed for the MD-simulated proteins using PTRAJ module. The generated pharmacophore models were used to screen a set of natural compounds and database compounds to select significant HITs. We conclude that the developed pharmacophore model can be a significant model for the identification of HITs as FTase inhibitors.     

Molecular dynamic simulations of electric microfield distributions in a nonideal electron-positron plasma

A symmetric model of a two-component plasma is considered and the distributions of electric microfields acting on charged and neutral particles are calculated using the method of molecular dynamics at a fixed temperature of T = 30000 K and different values of the coupling parameter 0.2 ≤ Γ ≤ 1.2. Changes in these distributions with varying Γ are discussed. Special attention is paid to the behavior of the distribution tails. The behavior of these tails at a neutral point is shown to agree with the tails of the Holtsmark distribution, whereas the tails of the distribution at a charge are considerably heavier and are characterized by the exponent that varies within the range from −2.2 up to −1.8 as Γ increases.     

Molecular dynamics simulations of water within models of ion channels.

The transbilayer pores formed by ion channel proteins contain extended columns of water molecules. The dynamic properties of such waters have been suggested to differ from those of water in its bulk state. Molecular dynamics simulations of ion channel models solvated within and at the mouths of their pores are used to investigate the dynamics and structure of intra-pore water. Three classes of channel model are investigated: a) parallel bundles of hydrophobic (Ala20) alpha-helices; b) eight-stranded hydrophobic (Ala10) antiparallel beta-barrels; and c) parallel bundles of amphipathic alpha-helices (namely, delta-toxin, alamethicin, and nicotinic acetylcholine receptor M2 helix). The self-diffusion coefficients of water molecules within the pores are reduced significantly relative to bulk water in all of the models. Water rotational reorientation rates are also reduced within the pores, particularly in those pores formed by alpha-helix bundles. In the narrowest pore (that of the Ala20 pentameric helix bundle) self-diffusion coefficients and reorientation rates of intra-pore waters are reduced by approximately an order of magnitude relative to bulk solvent. In Ala20 helix bundles the water dipoles orient antiparallel to the helix dipoles. Such dipole/dipole interaction between water and pore may explain how water-filled ion channels may be formed by hydrophobic helices. In the bundles of amphipathic helices the orientation of water dipoles is modulated by the presence of charged side chains. No preferential orientation of water dipoles relative to the pore axis is observed in the hydrophobic beta-barrel models.     

Molecular dynamics simulations

Molecular dynamics simulations have become a standard tool for the investigation of biomolecules. Simulations are performed of ever bigger systems using more realistic boundary conditions and better sampling due to longer sampling times. Recently, realistic simulations of systems as complex as transmembrane channels have become feasible. Simulations aid our understanding of biochemical processes and give a dynamic dimension to structural data; for example, the transformation of harmless prion protein into the disease-causing agent has been modeled.     

Molecular dynamics simulations of a DMSO/water mixture using the AMBER force field

Due to its protective properties of biological samples at low temperatures and under desiccation, dimethyl sulfoxide (DMSO) in aqueous solutions has been studied widely by many experimental approaches and molecular dynamics (MD) simulations. In the case of the latter, AMBER is among the most commonly used force fields for simulations of biomolecular systems; however, the parameters for DMSO published by Fox and Kollman in 1998 have only been tested for pure liquid DMSO. We have conducted an MD simulation study of DMSO in a water mixture and computed several structural and dynamical properties such as of the mean density, self-diffusion coefficient, hydrogen bonding and DMSO and water ordering. The AMBER force field of DMSO is seen to reproduce well most of the experimental properties of DMSO in water, with the mixture displaying strong and specific water ordering, as observed in experiments and multiple other MD simulations with other non-polarizable force fields.

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Graphical abstract Hydration structure within hydrogen-bonding distance around a DMSOmolecule

     

Molecular dynamics simulations of trihalomethanes removal from water using boron nitride nanosheets

Molecular dynamics simulations were performed to investigate the separation of trihalomethanes (THMs) from water using boron nitride nanosheets (BNNSs). The studied systems included THM molecules and a functionalized BNNS membrane immersed in an aqueous solution. An external pressure was applied to the z axis of the systems. Two functionalized BNNSs with large fluorinated-hydrogenated pore (F-H-pores) and small hydrogen-hydroxyl pore (H-OH-pores) were used. The pores of the BNNS membrane were obtained by passivating each nitrogen and boron atoms at the pore edges with fluorine and hydrogen atoms in the large pore or with hydroxyl and hydrogen atoms in the small pore. The results show that the BNNS with a small functionalized pore was impermeable to THM molecules, in contrast to the BNNS with a large functionalized pore. Using these membranes, water contaminants can be removed at lower cost.

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Graphical Abstract A snapshot of the simulation system. The BNNS membrane with the large functionalized pore is located in the middle of the box. The size of the box is 3 × 3 × 5 nm³. Green chlorine, cyan carbon, red oxygen, white hydrogen

     

Molecular dynamic simulations of the metallo-beta-lactamase from Bacteroides fragilis in the presence and absence of a tight-binding inhibitor

The beta-lactam-based antibiotics are among the most prescribed and effective antibacterial agents. Widespread use of these antibiotics, however, has created tremendous pressure for the emergence of resistance mechanisms in bacteria. The most common cause of antibiotic resistance is bacterial production of actamases that efficiently degrade antibiotics. The metallo-beta-lactamases are of particular clinical concern due to their transference between bacterial strains. We used molecular dynamics (MD) simulations to further study the conformational changes that occur due to binding of an inhibitor to the dicanzinc metallo-beta-lactamase from Bacteroides fragilis. Our studies confirm previous findings that the major flap is a major source of plasticity within the active site, therefore its dynamic response should be considered in drug development. However, our results also suggest the need for care in using MD simulations in evaluating loop mobility, both due to relaxation times and to the need to accurately model the zinc active site. Our study also reveals two new robust responses to ligand binding. First, there are specific localized changes in the zinc active site—a local loop flip—due to ligand intercalation that may be critical to the function of this enzyme. Second, inhibitor binding perturbs the dynamics throughout the protein, without otherwise perturbing the enzyme structure. These dynamic perturbations radiate outward from the active site and their existence suggests that long-range communication and dynamics may be important in the activity of this enzyme. Electronic supplementary material  The online version of this article (doi:) contains supplementary material, which is available to authorized users.     

Molecular dynamic simulations of the N-terminal receiver domain of NtrC reveal intrinsic conformational flexibility in the inactive state

The N-terminal receiver domain of NtrC is the molecular switch in the two-component signal transduction. It is the first protein where structures of both the active (phosphyroylated) and inactive (unphosphyroylated) states are determined experimentally. Phosphorylation of the NtrC at the active site induces large structural change. NMR experiments suggested that the wild type unphosphorylated NtrC adopts both the active and the inactive conformations and the phosphorylation stabilizes the active conformations. We applied free (unconstrained) molecular dynamic (MD) simulation to examine the intrinsic flexibilities and stabilities of the NtrC receiver domain in both the active and inactive conformations. Molecular dynamic simulations showed that the inactive state of NtrC receiver domain is more flexible than the active state. There were large movements in helix 4 and loop beta3-alpha3 which coincide with major structural differences between the inactive and active states. We observed large root-mean-square deviations from the initial starting structure and the large root-mean-square fluctuations during MD simulation for the inactive state. We then investigated the activation pathway with Targeted MD simulation. We show that the intrinsic flexibility in the loop beta3-alpha3 plays an important role in triggering the conformational change. Phosphorylation at the active site may serve to stabilize the conformational change. These results together suggest that the unphosphorylated NtrC receiver domain could be involved in a conformational equilibrium between two different states.     

Molecular dynamics simulations of the unfolding of an alpha-helical analogue of ribonuclease A S-peptide in water

Molecular dynamics simulations of the S-peptide analogue AETAAAKFLREHMDS have been conducted in aqueous solution for 300 ps at 278 K and for 500 ps in two different runs at 358 K. The results show agreement with experimental observations in that at low temperature, 5 degrees C, the helix is stable, while unfolding is observed at 85 degrees C. In the low-temperature simulation a solvent-separated ion pair was formed between Glu-2 and Arg-10, and the side chain of His-12 reoriented toward the C-terminal end of the alpha-helix. Detailed analyses of the unfolding pathways at high temperature have also revealed that the formation or disappearance of main-chain helical hydrogen bonds occurs frequently through an alpha in equilibrium with 3(10) in equilibrium with no hydrogen bond sequence.     

Molecular dynamics simulations of carrabiose

Molecular mechanics calculations have been performed for the disaccharide carrabiose, one of the repeat units of β-carrageenan, as a general model for the (1→4)-linkage in the carrageenans. An adiabatic conformational energy map for this unsulfated molecule was prepared by constrained energy minimization and compared to a previously reported rigid-residue energy map for the sulfated molecule and to a similar adiabatic map for neocarrabiose, the related (1→3)-linked dimer repeat unit of β-carrageenan. Molecular dynamics simulations of this molecule in vacuo and in an aqueous (TIP3P) solution were calculated, and the observed motions were found to be generally consistent with the vacuum adiabatic energy map. Unlike the case observed in previous simulations of neocarrabiose, little salvation shift in the molecular conformation was observed for carrabiose. From the dynamics, the linkage was observed to be relatively flexible, as has been inferred from experiment on sulfated carrageenan polymers. © 1997 John Wiley & Sons, Inc.     

Molecular dynamics simulations of xDNA

xDNA is a modified DNA, which contains natural as well as expanded bases. Expanded bases are generated by the addition of a benzene spacer to the natural bases. A set of AMBER force‐field parameters were derived for the expanded bases and the structural dynamics of the xDNA decamer ( xT5 ′ G xT A xC xG C xA xG T3′ ) · ( xA5′ C T xG C G xT A xC A3′) was explored using a 22 ns molecular dynamics simulation in explicit solvent. During the simulation, the duplex retained its Watson‐Crick base‐pairing and double helical structure, with deviations from the starting B‐form geometry towards A‐form; the deviations are mainly in the backbone torsion angles and in the helical parameters. The sugar pucker of the residues were distributed among a variety of modes; C2′ endo, C1′ exo, O4′ endo, C4′ exo, C2′ exo, and C3′ endo. The enhanced stacking interactions on account of the modification in the bases could help to retain the duplex nature of the helix with minor deviations from the ideal geometry. In our simulation, the xDNA showed a reduced minor groove width and an enlarged major groove width in comparison with the NMR structure. Both the grooves are larger than that of standard B‐DNA, but major groove width is larger than that of A‐DNA with almost equal minor groove width. The enlarged groove widths and the possibility of additional hydration in the grooves makes xDNA a potential molecule for various applications. © 2009 Wiley Periodicals, Inc. Biopolymers 91: 351–360, 2009. This article was originally published online as an accepted preprint. The “Published Online” date corresponds to the preprint version. You can request a copy of the preprint by emailing the Biopolymers editorial office at biopolymers@wiley.com     

Molecular simulations of rhodopsin tetrameter

Di/oligomerization of G-protein coupled receptors (GPCRs) is well established, however very little is known regarding the interaction details. Current paper presents results of molecular dynamics simulations of theoretical model of rhodopsin tetramer with transducine (Gt) in lipid bilayer. Ligand-protein and receptor-receptor interactions have been proposed.