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Concept: Molecular mechanics


Proper treatment of nonbonded interactions is essential for the accuracy of molecular dynamics (MD) simulations, especially in studies of lipid bilayers. The use of the CHARMM36 force field (C36 FF) in different MD simulation programs can result in disagreements with published simulations performed with CHARMM due to differences in the protocols used to treat the long-range and 1-4 nonbonded interactions. In this study, we systematically test the use of the C36 lipid FF in NAMD, GROMACS, AMBER, OpenMM, and CHARMM/OpenMM. A wide range of Lennard-Jones (LJ) cutoff schemes and integrator algorithms were tested to find the optimal simulation protocol to best match bilayer properties of six lipids with varying acyl chain saturation and head groups. MD simulations of a 1,2-dipalmitoyl-sn-phosphatidylcholine (DPPC) bilayer were used to obtain the optimal protocol for each program. MD simulations with all programs were found to reasonably match the DPPC bilayer properties (surface area per lipid, chain order parameters, and area compressibility modulus) obtained using the standard protocol used in CHARMM as well as from experiments. The optimal simulation protocol was then applied to the other five lipid simulations and resulted in excellent agreement between results from most simulation programs as well as with experimental data. AMBER compared least favorably with the expected membrane properties, which appears to be due to its use of the hard-truncation in the LJ potential versus a force-based switching function used to smooth the LJ potential as it approaches the cutoff distance. The optimal simulation protocol for each program has been implemented in CHARMM-GUI. This protocol is expected to be applicable to the remainder of the additive C36 FF including the proteins, nucleic acids, carbohydrates, and small molecules.

Concepts: Molecular dynamics, Lipid, Molecular mechanics, CHARMM, Force field, GROMACS, Force field implementation, OPLS


Lysozyme is a well-studied enzyme that hydrolyzes the β-(1,4)-glycosidic linkage of N-acetyl-β-glucosamine (NAG)(n) oligomers. The active site of hen egg-white lysozyme (HEWL) is believed to consist of six subsites, A-F that can accommodate six sugar residues. We present studies exploring the use of polarizable force fields in conjunction with all-atom molecular dynamics (MD) simulations to analyze binding structures of complexes of lysozyme and NAG trisaccharide, (NAG)(3) . MD trajectories are applied to analyze structures and conformation of the complex as well as protein-ligand interactions, including the hydrogen-bonding network in the binding pocket. Two binding modes (ABC and BCD) of (NAG)(3) are investigated independently based on a fixed-charge model and a polarizable model. We also apply molecular mechanics with generalized born and surface area (MM-GBSA) methods based on MD using both nonpolarizable and polarizable force fields to compute binding free energies. We also study the correlation between root-mean-squared deviation and binding free energies of the wildtype and W62Y mutant; we find that for this prototypical system, approaches using the MD trajectories coupled with implicit solvent models are equivalent for polarizable and fixed-charge models. © 2012 Wiley Periodicals, Inc.

Concepts: Protein, Molecular dynamics, Computational chemistry, Force, Molecular modelling, Implicit solvation, Molecular mechanics, Water model


We provide theoretical predictions of the intrinsic stability of different arrangements of guanine quadruplex (G-DNA) stems. Most computational studies of nucleic acids have applied Molecular Mechanics (MM) approaches using simple pairwise-additive force fields. The principle limitation of such calculations is the highly approximate nature of the force fields. In this study we for the first time apply accurate QM computations (DFT-D3 with large atomic orbital basis sets) to essentially complete DNA building blocks, namely, seven different folds of the cation-stabilized 2-quartet G-DNA stem, each having more than 250 atoms. The solvent effects are approximated by COSMO continuum solvent. We reveal sizeable differences between MM and QM descriptions of relative energies of different G-DNA stems, which apparently reflect approximations of the DNA force field. Using the QM energy data, we propose correction to earlier free energy estimates of relative stabilities of different parallel, hybrid and antiparallel G-stem folds based on classical simulations. The new energy ranking visibly improves the agreement between theory and experiment. We predict the 5'-anti-anti-3' GpG dinucleotide step to be the most stable one, closely followed by the 5'-syn-anti-3' step. The results are in good agreement with known experimental structures of 2, 3 and 4-quartet G-DNA stems. Besides providing specific results for G-DNA, our study highlights basic limitations of force field modeling of nucleic acids. Although QM computations have their own limitations, mainly the lack of conformational sampling and the approximate description of the solvent, they can substantially improve quality of calculations currently relying exclusively on force fields.

Concepts: DNA, Molecular dynamics, Nucleic acid, Computational chemistry, Adenine, Classical mechanics, Guanine, Molecular mechanics


Rho-associated protein kinases (ROCK1 and ROCK2) are promising targets for a number of diseases, including cardiovascular disorders, nervous system diseases, cancers, etc. Recently, we have successfully identified a ROCK1 inhibitor () with the triazine core. In order to gain a deeper insight into the microscopic binding of this inhibitor with ROCK1 and design derivatives with improved potency, the interactions between ROCK1 and a series of triazine/pyrimidine-based inhibitors were studied by using an integrated computational protocol that combines molecular docking, molecular dynamics (MD) simulations, binding free energy calculations, and binding energy decomposition analysis. First, three docking protocols, rigid receptor docking, induced fit docking, QM-polarized ligand docking, were used to determine the binding modes of the studied inhibitors in the active site of ROCK1. The results illustrate that rigid receptor docking achieves the best performance to rank the binding affinities of the studied inhibitors. Then, based on the predicted structures from molecular docking, MD simulations and MM/GBSA free energy calculations were employed to determine the dynamic binding process and compare the binding modes of the inhibitors with different activities. The binding free energies predicted by MM/GBSA are in good agreement with the experimental bioactivities, and the analysis of the individual energy terms suggests that the van der Waals interaction is the major driving force for ligand binding. In addition, the residue-inhibitor interaction spectra were obtained by the MM/GBSA free energy decomposition analysis, and the important residues for achieving strong binding were highlighted, which affords important guidance for the rational design of novel ROCK inhibitors. Finally, a variety of derivatives of inhibitor were designed and four of them showed promising potency according to the predictions. We expect that our study can provide significant insight into the development of improved inhibitors of ROCK1.

Concepts: Molecular dynamics, Mass, Computational chemistry, Enzyme inhibitor, Docking, Molecular mechanics, Binding energy, Docking@Home


Thirteen 2-[2-(5-methyl-2-benzoxazolinone-3-yl)acetyl]-¾/5-substituted benzylidenehydrazine derivatives were synthesized by reacting 2-(5-methyl-2-benzoxazolinone-3-yl)acetylhydrazine and substituted benzaldehydes in neutral and acid/base catalyzed conditions, and a comparison was made in terms of their yields and reaction times. The structures of all compounds were confirmed by IR, (1)H NMR, (13)C NMR, mass spectral data, and elemental analyses. All the compounds were investigated for their ability to selectively inhibit MAO isoforms by in vitro tests and were found to inhibit recombinant human MAO-B selectively and reversibly in a competitive manner. Among the compounds examined, compound 16 was found to be more selective than selegiline, a known MAO-B inhibitor, in respect to the K ( i ) values experimentally found. Additionally, compounds 9 and 15 showed moderate MAO-B inhibitor activity. The interaction of compounds with MAO isoforms was investigated by molecular docking studies using recently published crystallographic models of MAO-A and MAO-B. The results obtained from the docking studies were found to be in good agreement with the experimental values.

Concepts: Chemical reaction, Computational chemistry, Enzyme inhibitor, Neurotransmitter, Xanthine oxidase inhibitor, Monoamine oxidase, Molecular modelling, Molecular mechanics


In accordance with our antiviral drug development attempt, acylhydrazone derivatives bearing amino acid side chains were synthesized for the evaluation of their antiviral activity against various types of viruses. Among these compounds, 8(S) , 11(S) , and 12(S) showed anti-HIV-1 activity with a 50% inhibitory concentration (IC(50) ) = 123.8 µM (selectivity index, SI > 3), IC(50)  = 12.1 µM (SI > 29), IC(50)  = 17.4 µM (SI > 19), respectively. Enantiomers 8® , 11® , and 12® were inactive against the HIV-1 strain III(B) . Hydrazones 8(S) , 11(S) , and 12(S) which were active against HIV-1 wild type showed no inhibition against a double mutant NNRTI-resistant strain (K103N;Y181C). Molecular docking calculations of R- and S-enantiomers of 8, 11, and 12 were performed using the hydrazone-bound novel site of HIV-1 RT.

Concepts: Gene, Amino acid, Virus, Influenza, Computational chemistry, Enzyme inhibitor, Molecular modelling, Molecular mechanics


The interaction of pepsin with chlorogenic acid (CHA) was investigated using fluorescence, UV/vis spectroscopy and molecular modeling methods. Stern-Volmer analysis indicated that the fluorescence quenching of pepsin by CHA resulted from a static mechanism, and the binding constant was 1.1846 × 10(5) and 1.1587 × 10(5) L/mol at 288 and 310 K, respectively. The distance between donor (pepsin) and acceptor (CHA) was calculated to be 2.39 nm and the number of binding sites for CHA binding on pepsin was ~ 1. The results of synchronous fluorescence and three-dimensional fluorescence showed that binding of CHA to pepsin could induce conformational changes in pepsin. Molecular docking experiments found that CHA bonded with pepsin in the area of the hydrophobic cavity with Van der Waals' forces or hydrogen bonding interaction, which were consistent with the results obtained from the thermodynamic parameter analysis. Furthermore, the binding of CHA can inhibit pepsin activity in vitro. Copyright © 2013 John Wiley & Sons, Ltd.

Concepts: Fluorescence, Spectroscopy, Oxygen, Hydrogen, Atom, Computational chemistry, Molecular modelling, Molecular mechanics


Bromomethane (CH3Br) is an acutely toxic environmental pollutant that contributes to ozone depletion. Molecular simulation could be a valuable tool for studying its partitioning and transport in the environment if an accurate molecular model was available. The Generalized Amber Force Field (GAFF), OPLS (Optimized Potentials for Liquid Simulations) force field, and CHARMM General Force Field (CGenFF) were tested for their ability to model the physical properties of liquid bromomethane. The OPLS force field was in fairly good agreement with experiment, while CGenFF and GAFF were significantly in error. The Br Lennard-Jones parameters of the GAFF and CGenFF models were reparameterized, but their radial distribution functions still have significant deviations from those calculated by Ab Initio Molecular Dynamics (AIMD). A Drude polarizable force field for bromomethane was parameterized with an off-center positively charged site to represent the C-Br σ-hole. This model is in good agreement with the bulk physical properties and the AIMD RDFs. The modest solubility of bromomethane was reproduced by this model, with dispersion interactions being the dominant water-solute interaction. The water- solute electrostatic interactions are a smaller factor in solubility. This model predicts bromomethane to have a 13 kJ/mol surface excess potential at the water-vapor interface.

Concepts: Electric charge, Molecular dynamics, Computational chemistry, Molecular modelling, Molecular mechanics, AMBER, Force field, GROMACS


Lipoxygenases (LOXs), key enzymes involved in the biosynthesis of leukotrienes, are well known to participate in the inflammatory and immune responses. With the recent reports of involvement of 5-LOX (one of the isozyme of LOX in human) in cancer, there is a need to find out selective inhibitors of 5-LOX for their therapeutic application. In the present study, plant derived 300 anti-inflammatory and anti-cancerous secondary metabolites (100 each of alkaloids, flavonoids and terpenoids) have been screened for their pharmacokinetic properties and subsequently docked for identification of potent inhibitors of 5-LOX. Pharmacokinetic analyses revealed that only 18 alkaloids, 26 flavonoids and 9 terpenoids were found to fulfill all the ADMET descriptors as well as those of Lipinski’s Rule of Five. Docking analyses of pharmacokinetically screened metabolites and their comparison with a known inhibitor (drug), namely zileuton revealed that only 3 alkaloids, 6 flavonoids and 3 terpenoids were found to dock successfully with 5-LOX with the flavonoid, velutin being the most potent inhibitor among all. The results of the docking analyses were further validated by performing molecular dynamics simulation and binding energy calculations for the complexes of 5-LOX with velutin, galangin, chrysin (in order of LibDock scores) and zileuton. The data revealed stabilization of all the complexes within 15 nanoseconds of simulation with velutin complex exhibiting least RMSD value (0.285 ± 0.007 nm) as well as least binding energy (ΔGbind = -203.169 kJ/mol) as compared to others during the stabilization phase of simulation.

Concepts: Inflammation, Pharmacology, Metabolism, Molecular dynamics, Computational chemistry, Enzyme inhibitor, Docking, Molecular mechanics


Micelles play an important role in both experimental and computational studies of the effect of lipid interactions on biological systems. The spherical geometry and the dynamical behavior of micelles makes generating micelle structures for use in molecular simulations challenging. An easy tool for generating simulation-ready micelle models, covering a broad range of lipids, is highly desirable. Here, we present a new Web server, Micelle Maker, which can provide equilibrated micelle models as a direct input for subsequent molecular dynamics simulations from a broad range of lipids (currently 25 lipid types, including 24 glycolipids). The Web server, which is available at, uses error checking routines to prevent clashes during the initial placement of the lipids and uses AMBER’s GLYCAM library for generating minimized or equilibrated micelle models, but the resulting structures can be used as starting points for simulations with any force field or simulation package. Extensive validation simulations with an overall simulation time of 12 μs using eight micelle models where assembly information is available show that all of the micelles remain very stable over the whole simulation time. Finally, we discuss the advantages of Micelle Maker relative to other approaches in the field.

Concepts: Molecular dynamics, Computational chemistry, Lipid, Monte Carlo method, Micelle, Computer simulation, Molecular mechanics, AMBER