Computer Simulation of Liquid Methanol II. System Size Effects

Abstract

A series of molecular dynamics simulations of liquid methanol has been carried out on a supernode transputer array. Four system sizes from 125 to 512 molecules have been considered, in order to study the effect of system size on the calculated structural, orientational and dynamic properties. The dielectric constant and the dielectric relaxation time are compared with experimental data.     

In silico identification of potential inhibitors against main protease of SARS-CoV-2 6LU7 from Andrographis panniculata via molecular docking,binding energy calculations and molecular dynamics simulation studies

BackgroundThe ongoing global outbreak of new corona virus (SARS-CoV-2) has been recognized as global public health concern since it causes high morbidity and mortality every day. Due to the rapid spreading and re-emerging, we need to find a potent drug against SARS-CoV-2. Synthetic drugs, such as hydroxychloroquine, remdisivir have paid more attention and the effects of these drugs are still under investigation, due to their severe side effects. Therefore, the aim of the present study was performed to identify the potential inhibitor against main protease SARS-CoV-2 6LU7.ObjectiveIn this study, RO5, ADME properties, molecular dynamic simulations and free binding energy prediction were mainly investigated.ResultsThe molecular docking study findings revealed that andrographolide had higher binding affinity among the selected natural diterpenoids compared to co-crystal native ligand inhibitor N3. The persistent inhibition of Ki for diterpenoids was analogous. Furthermore, the simulations of molecular dynamics and free binding energy findings have shown that andrographolide possesses a large amount of dynamic properties such as stability, flexibility and binding energy.ConclusionIn conclusion, findings of the current study suggest that selected diterpenoids were predicted to be the significant phytonutrient-based inhibitor against SARS-CoV-2 6LU7 (M^pro). However, preclinical and clinical trials are needed for the further scientific validation before use.     

Conformational ensemble of an intrinsically flexible loop in mitochondrial import protein Tim21 studied by modeling and molecular dynamics simulations

BackgroundTim21, a subunit of a highly dynamic translocase of the inner mitochondrial membrane (TIM23) complex, translocates proteins by interacting with subunits in the translocase of the outer membrane (TOM) complex and Tim23 channel in the TIM23 complex. A loop segment in Tim21, which is in close proximity of the binding site of Tim23, has different conformations in X-ray, NMR and new crystal contact-free space (CCFS) structures. MD simulations can provide information on the structure and dynamics of the loop in solution.MethodsThe conformational ensemble of the loop was characterized using loop modeling and molecular dynamics (MD) simulations.ResultsMD simulations confirmed mobility of the loop. Multidimensional scaling and clustering were used to characterize the dynamic conformational ensemble of the loop. Free energy landscape showed that the CCFS crystal structure occupied a low energy region as compared to the conventional X-ray crystal structure. Analysis of crystal packing indicates that the CCFS provides larger conformational space for the motions of the loop.ConclusionsOur work reported the conformational ensemble of the loop in solution, which is in agreement with the structure obtained from CCFS approach. The combination of the experimental techniques and computational methods is beneficial for studying highly flexible regions of proteins.General significanceComputational methods, such as loop modeling and MD simulations, have proved to be useful for studying conformational flexibility of proteins. These methods in integration with experimental techniques such as CCFS has the potential to transform the studies on flexible regions of proteins.     

Computational investigations of gram-negative bacteria phosphopantetheine adenylyltransferase inhibitors using 3D-QSAR,molecular docking and molecular dynamic simulations

Abstract

Phosphopantetheine adenylyltransferase (PPAT) has been recognized as a promising target to develop novel antimicrobial agents, which is a hexameric enzyme that catalyzes the penultimate step in coenzyme A biosynthesis. In this work, molecular modeling study was performed with a series of PPAT inhibitors using molecular docking, three-dimensional qualitative structure-activity relationship (3D-QSAR) and molecular dynamic (MD) simulations to reveal the structural determinants for their bioactivities. Molecular docking study was applied to understand the binding mode of PPAT with its inhibitors. Subsequently, 3D-QSAR model was constructed to find the features required for different substituents on the scaffolds. For the best comparative molecular field analysis (CoMFA) model, the Q² and R² values of which were calculated as 0.702 and 0.989, while they were calculated as 0.767 and 0.983 for the best comparative molecular similarity index analysis model. The statistical data verified the significance and accuracy of our 3D-QSAR models. Furthermore, MD simulations were carried out to evaluate the stability of the receptor–ligand contacts in physiological conditions, and the results were consistent with molecular docking studies and 3D-QSAR contour map analysis. Binding free energy was calculated with molecular mechanics generalized born surface area approach, the result of which coincided well with bioactivities and demonstrated that van der Waals accounted for the largest portion. Overall, our study provided a valuable insight for further research work on the recognition of potent PPAT inhibitors.

Communicated by Ramaswamy H. Sarma     

Differential interactions of the antimicrobial peptide,RQ18, with phospholipids and cholesterol modulate its selectivity for microorganism membranes

BackgroundAntimicrobial peptides (AMPs) are molecules with potential application for the treatment of microorganism infections. We, herein, describe the structure, activity, and mechanism of action of RQ18, an α-helical AMP that displays antimicrobial activity against Gram-positive and Gram-negative bacteria, and yeasts from the Candida genus.MethodsA physicochemical-guided design assisted by computer tools was used to obtain our lead peptide candidate, named RQ18. This peptide was assayed against Gram-positive and Gram-negative bacteria, yeasts, and mammalian cells to determine its selectivity index. The secondary structure and the mechanism of action of RQ18 were investigated using circular dichroism, large unilamellar vesicles, and molecular dynamic simulations.ResultsRQ18 was not cytotoxic to human lung fibroblasts, peripheral blood mononuclear cells, red blood cells, or Vero cells at MIC values, exhibiting a high selectivity index. Circular dichroism analysis and molecular dynamic simulations revealed that RQ18 presents varying structural profiles in aqueous solution, TFE/water mixtures, SDS micelles, and lipid bilayers. The peptide was virtually unable to release carboxyfluorescein from large unilamellar vesicles composed of POPC/cholesterol, model that mimics the eukaryotic membrane, indicating that vesicles' net charges and the presence of cholesterol may be related with RQ18 selectivity for bacterial and fungal cell surfaces.ConclusionsRQ18 was characterized as a membrane-active peptide with dual antibacterial and antifungal activities, without compromising mammalian cells viability, thus reinforcing its therapeutic application.General significanceThese results provide further insight into the complex process of AMPs interaction with biological membranes, in special with systems that mimic prokaryotic and eukaryotic cell surfaces.     

Molecular Dynamics of Phenylalanine Transfer RNA

Abstract

The atomic motions of yeast phenylalanine transfer RNA have been simulated using the molecular dynamics algorithm. Two simulations were carried out for a period of 12 picoseconds, one with a normal Van der Waals potential and the other with a modified Van der Waals potential intended to mimic the effect of solvent. An analysis of large scale motions, surface exposure, root mean square displacements, helical oscillations and relaxation mechanisms reveals the maintenance of stability in the simulated structures and the general similarity of the various dynamic features of the two simulations. The regions of conformational flexibility and rigidity for tRNA^Phe have been shown in a quantitative measure through this approach.     

Investigations of Nematic-Isotropic Transition by Means of Constant Pressure Molecular Dynamics Simulations

Abstract

Constant pressure molecular dynamics simulations, which secure the system to be under hydrostatic pressure, are used to simulate the behavior of liquid crystals consisting of anisotropic molecules with both translational and orientational freedom. In order to investigate to what extent can the properties known to real liquid crystalline phases be explained by the anisotropy of the shape of the molecules alone, the molecular dynamic (MD) simulation uses purely repulsive short-range pair potentials representing soft spherocylinders. A clear change in the microscopic as well as the macroscopic physical properties are observed near the phase transition from nematic liquid crystal to isotropic liquid.     

Dynamic molecules: molecular dynamics for everyone. An internet-based access to molecular dynamic simulations: basic concepts

Molecular dynamics is a rapidly developing field of science and has become an established tool for studying the dynamic behavior of biomolecules. Although several high quality programs for performing molecular dynamic simulations are freely available, only well-trained scientists are currently able to make use of the broad scientific potential that molecular dynamic simulations offer to gain insight into structural questions at an atomic level. The "Dynamic Molecules" approach is the first internet portal that provides an interactive access to set up, perform and analyze molecular dynamic simulations. It is completely based on standard web technologies and uses only publicly available software. The aim is to open molecular dynamics techniques to a broader range of users including undergraduate students, teachers and scientists outside the bioinformatics field. The time-limiting factors are the availability of free capacity on the computing server to run the simulations and the time required to transport the history file through the internet for the animation mode. The interactive access mode of the portal is acceptable for animations of molecules having up to about 500 atoms.Figure Several main menus (see top) are provided to start "New Simulations", to "Display Simulations" and to "Analyze" statistical and geometrical properties of the molecule. Here the "Display Simulation" interface is shown. The Chime plugin is used to visualize molecular 3D structures and motions.     

On the Information Content of Protein Sequences

Abstract

TATA-box binding protein (TBP) in a monomelic form and the complexes it forms with DNA have been elucidated with molecular dynamics simulations. Large TBP domain motions (bend and twist) are detected in the monomer as well as in the DNA complexes; these motions can be important for TBP binding of DNA. TBP interacts with guanine bases flanking the TATA element in the simulations of the complex; these interactions may explain the preference for guanine observed at these DNA positions. Side chains of some TBP residues at the binding interface display significant dynamic flexibility that results in ‘flipflop’ contacts involving multiple base pairs of the DNA. We discuss the possible functional significance of these observations.     

100ps Molecular Dynamic Simulation of d(TATCACC)2

Abstract

A heptanucleotide sequence d(TATCACC)2 from OR3 region of bacteriophage X is considered sufficient for the recognition of Cro protein. We present here results on molecular dynamic simulations on this sequence for 100 ps in 0.02 ps interval. The simulations are done using computer program GROMOS. The conformational results are averaged over each ps. The IUPAC torsional parameters for 100 conformations are illustrated using a wheal and a dial systems. Several other stereochemical parameters such as H-bonding lengths and angles, sugar puckers, helix twist and roll angles as also distances between opposite strand phosphorus are depicted graphically. We find that there is rupture of terminal H-bonds. The bases are tilted and shifted away from the helix axis giving rise to bifurcated H-bonds. H- bonds are seen even in between different base pairs. The role of these dynamic structural changes in the recognition of OR3 operator by Cro protein is discussed in the paper.     

Isobaric and Isothermal Molecular Dynamics Simulations of Diatomic Systems

Abstract

Isobaric molecular dynamics simulations were carried out for diatomic systems using different algorithms available in the literature. Two-centered Lennard-Jones potentials with and without quadrupolar interactions were used. Thermodynamic properties obtained from the isobaric algorithms compared very well with those of an equivalent simulation in the microcanonical ensemble; however, some differences were observed when similar comparisons were carried out for dynamic properties. More specifically, the constant pressure constraint affects the translational dynamics of the system because of the non-negligible differences between the momenta and the instantaneous velocities of the molecules.

Furthermore, the following studies were carried out using isobaric MD simulations: 1. Low temperature spontaneous FCC-orthorhombic (and vice versa) transition of a diatomic system with quadrupolar interactions as a function of the molecular bond length. 2. Effect of quadrupolar interaction on isobaric melting of a model diatomic system. 3. Effect of pressure on melting properties of a model diatomic system with quadrupolar interactions.     

Molecular Dynamics Investigation of the Lamellar Liquid-Crystal D-Phase in the Octylammonium Chloride/Water System

Abstract

The two-component cationic surfactant system octylammonium chloride/water (20/80 mole percent) has been investigated by molecular dynamics simulations using an intermolecular force field taken from the literature. The multi-lamella bilayer structure is demonstrated to be stable over a nanosecond molecular dynamics trajectory and to possess physical characteristics in reasonable accord with available experimental data. The results are sufficiently encouraging that further studies of this system seem warranted.     

Comparison of Different Three-site Interaction Potentials for Liquid Acetonitrile

Abstract

Computer simulations of liquid acetonitrile at normal room conditions are reported. Both static and dynamic properties are analysed. Special attention is paid to the dielectric properties. A three-site interaction potential has been derived from ab initio calculations on the gas phase dimer and a comparison with different three-site interaction potentials available in the literature is presented. The suitability of three-site models to reproduce the properties of the real liquid is discussed by comparing computer simulation results with experimental data.     

Orientation and Dynamics of Peptides in Membranes Calculated from H-NMR Data

Solid-state ²H-NMR is routinely used to determine the alignment of membrane-bound peptides. Here we demonstrate that it can also provide a quantitative measure of the fluctuations around the distinct molecular axes. Using several dynamic models with increasing complexity, we reanalyzed published ²H-NMR data on two representative α-helical peptides: 1), the amphiphilic antimicrobial peptide PGLa, which permeabilizes membranes by going from a monomeric surface-bound to a dimeric tilted state and finally inserting as an oligomeric pore; and 2), the hydrophobic WALP23, which is a typical transmembrane segment, although previous analysis had yielded helix tilt angles much smaller than expected from hydrophobic mismatch and molecular dynamics simulations. Their ²H-NMR data were deconvoluted in terms of the two main helix orientation angles (representing the time-averaged peptide tilt and azimuthal rotation), as well as the amplitudes of fluctuation about the corresponding molecular axes (providing the dynamic picture). The mobility of PGLa is found to be moderate and to correlate well with the respective oligomeric states. WALP23 fluctuates more vigorously, now in better agreement with the molecular dynamics simulations and mismatch predictions. The analysis demonstrates that when ²H-NMR data are fitted to extract peptide orientation angles, an explicit representation of the peptide rigid-body angular fluctuations should be included.     

Recent advances in maximum entropy biasing techniques for molecular dynamics

ABSTRACT

This review describes recent advances by the authors and others on the topic of incorporating experimental data into molecular simulations through maximum entropy methods. Methods which incorporate experimental data improve accuracy in molecular simulation by minimally modifying the thermodynamic ensemble. This is especially important where force fields are approximate, such as when employing coarse-grain models, or where high accuracy is required, such as when attempting to mimic a multiscale self-assembly process. The authors review here the experiment directed simulation (EDS) and experiment directed metadynamics (EDM) methods that allow matching averages and distributions in simulations, respectively. Important system-specific considerations are discussed such as using enhanced sampling simultaneously, the role of pressure, treating uncertainty, and implementations of these methods. Recent examples of EDS and EDM are reviewed including applications to ab initio molecular dynamics of water, incorporating environmental fluctuations inside of a macromolecular protein complex, improving RNA force fields, and the combination of enhanced sampling with minimal biasing to model peptides     

MD Simulations of Liquids with Td,Oh Molecular Symmetry

Abstract

A new method is proposed for the calculation of intermolecular interactions in Molecular Dynamics simulations of liquids with T_d, O_h molecular symmetry. The new algorithm is based on the separation of the pair potential into a short-range and a long-range contribution described by a site-site and a spherical centre-centre potential model respectively using an additional cutoff distance. Test calculations for the Lennard-Jones fluids CCl₄ and SF₆ show significant savings in CPU time. We compare thermodynamic properties, pair correlation functions and a few dynamic autocorrelation functions obtained with the novel strategy with results of the commonly used algorithm for systems containing 864 molecules. Since no significant differences appear the new algorithm may be suggested as a useful contribution to the area of Molecular Dynamics simulation of liquids with these rather high molecular symmetries.     

Simulating the free energy of passive membrane permeation for small molecules

Abstract

Computer simulations of passive membrane permeation provide important microscopic insights into the molecular mechanism of this important biological process that are complementary to experimental data. Our review focuses on the main approaches for calculating the free energy, or potential of mean force, for permeation of small molecules through lipid bilayers. The theoretical background for most currently used methods for potential of mean force calculation is described, including particle insertion, thermodynamic integration, umbrella sampling, metadynamics, adaptive biasing force and milestoning. A brief comparison of strengths and weaknesses of the competing approaches is presented. This is followed by a survey of results obtained by the different methods, with special attention to describing the mechanistic insights generated by modelling and illustrating capabilities of the different techniques. We conclude with a discussion of recent advances and future directions in modelling membrane permeation, including latest methodological enhancements, consideration of multiple slow variables and memory effects.     

A Combined 2D-NMR and Molecular Dynamics Analysis of the Structure of the Actinomycin D: d(ATGCAT)2 Complex

Abstract

We present a comparative analysis of an NMR experiment and molecular and harmonic dynamics simulations of an actinomycin D: d(ATGCAT)₂ complex. A comparison of NOE measurements and 1/R⁶ weighted proton-proton distances confirm the general correctness of the Actinomycin D-DNA model proposed by Sobell. There are, however, some substantial differences between the proton-proton distances inferred from the NOE results and the molecular and harmonic dynamics simulations. The remaining discrepancies could either come from contributions of other conformations to the average properties of the complex or from uncertainties in the NMR distance analysis. An analysis of the molecular dynamics helix properties, sugar puckers, hydrogen bonding, rms fluctuations and torsional properties are qualitatively consistent with those from previous simulations, but the presence of an intercalated drug leads to some new structural and dynamical features.