New QM/MM implementation of the DFTB3 method in the gromacs package

The approximate density‐functional tight‐binding theory method DFTB3 has been implemented in the quantum mechanics/molecular mechanics (QM/MM) framework of the Gromacs molecular simulation package. We show that the efficient smooth particle–mesh Ewald implementation of Gromacs extends to the calculation of QM/MM electrostatic interactions. Further, we make use of the various free‐energy functionalities provided by Gromacs and the PLUMED plugin. We exploit the versatility and performance of the current framework in three typical applications of QM/MM methods to solve biophysical problems: (i) ultrafast proton transfer in malonaldehyde, (ii) conformation of the alanine dipeptide, and (iii) electron‐induced repair of a DNA lesion. Also discussed is the further development of the framework, regarding mostly the options for parallelization. © 2015 Wiley Periodicals, Inc.     

Inspection on the Mechanism of SARS-CoV-2 Inhibition by Penciclovir: A Molecular Dynamic Study

In recent years, humanity has had to face a critical pandemic due to SARS-CoV-2. In the rapid search for effective drugs against this RNA-positive virus, the repurposing of already existing nucleotide/nucleoside analogs able to stop RNA replication by inhibiting the RNA-dependent RNA polymerase enzyme has been evaluated. In this process, a valid contribution has been the use of in silico experiments, which allow for a rapid evaluation of the possible effectiveness of the proposed drugs. Here we propose a molecular dynamic study to provide insight into the inhibition mechanism of Penciclovir, a nucleotide analog on the RNA-dependent RNA polymerase enzyme. Besides the presented results, in this article, for the first time, molecular dynamic simulations have been performed considering not only the RNA-dependent RNA polymerase protein, but also its cofactors (fundamental for RNA replication) and double-strand RNA.     

StreaMD: Advanced analysis of molecular dynamics using R

Gromacs is one of the most popular molecular simulation suites currently available. In this contribution we present streaMD , the first interface between Gromacs trajectory files and the statistical language R . The amount of data created due to ever increasing computational power renders fast and efficient analysis of trajectories into a challenge. Especially as standard approaches such as root‐mean square fluctuations and the like provide only limited physical insight. In our streaMD package integration of the Gromacs I/O libraries with advanced, graph‐based analysis methods as the java library Stream leads to both: improved speed and analysis depth. We benchmark our results and highlight the applicability of the package by an interesting problem in RNA design, namely the interaction of tetracycline with an aptamer. © 2018 Wiley Periodicals, Inc.     

The flying ice cube: Velocity rescaling in molecular dynamics leads to violation of energy equipartition

This article describes an unexpected phenomenon encountered during MD simulations: velocity rescaling using standard protocols can systematically change the proportion of total kinetic energy (KE) found in motions associated with the various degrees of freedom. Under these conditions, the simulation violates the principle of equipartition of energy, which requires a mean kinetic energy of RT/2 in each degree of freedom. A particularly pathological form of this problem occurs if one does not periodically remove the net translation of (and rotation about) the center of mass. In this case, almost all of the kinetic energy is converted into these two kinds of motion, producing a system with almost no kinetic energy associated with the internal degrees of freedom. We call this phenomenon “the flying ice cube.” We present a mathematical analysis of a simple diatomic system with two degrees of freedom, to document the origin of the problem. We then present examples from three kinds of MD simulations, one being an in vacuo simulation on a diatomic system, one involving a low resolution model of DNA in vacuo, and the third using a traditional all-atom DNA model with full solvation, periodic boundary conditions, and the particle mesh Ewald method for treating long-range electrostatics. Finally, we discuss methods for avoiding the problem. © 1998 John Wiley & Sons, Inc. J Comput Chem 19: 726–740, 1998     

基于分子动力学模拟的表面活性剂力场界面的构建及分析

以计算机模拟真实环境,根据分子动力学模拟原理以及相关应用,提出了使用分子优化软件,将分割后的分子片段在ATB网站上进行最终优化及拓扑文件的整合,并对抗盐性进行了试验验证,用在构建的界面中研究表面活性剂的活动轨迹以及离子对于此类表面活性剂的影响。在模拟过程中加入同一含量的Mg2+、Ca2+,考察这两种新型甜菜碱型两性离子表面活性剂在油水界面的密度分布及活动行为,从而研究表面活性剂结构和抗盐性之间的关系。研究结果表明,钙离子对NONA-CH3型甜菜碱界面行为的影响更为显著,它的抗盐性顺序为Na+Mg2+Ca2+;在相同外界条件下,NONA-CH2CH3的抗盐性能更优异。     

Dynamics of a Spreading Nanodroplet: A Molecular Dynamic Simulation

The spreading of polymer nanodroplets upon a sudden change from partial to complete wetting on an ideally flat and structureless solid substrate has been studied by molecular dynamic simulations using a coarse‐grained bead‐spring model of flexible macromolecules. Tanner's law for the growth of the lateral droplet radius {R(t) ∝ t^0.1} is found to hold as long as the droplet does not disintegrate into individually moving chains. The data for the contact angle θ following from Tanner's law correspond to a dependence on time {θ(t) ∝ t^−0.3}. Our analysis of the mean square displacements of the polymer centers of mass reveals several dynamic regimes during the process of spreading. PACS numbers: 68.10.Gw, 05.70.Ln, 61.20.Ja, 8.45.Gd.

Molecular dynamics results for the average mean square displacement of all polymer chains plotted vs. time for a broad range of values for ε_wall.     

Pyrite: A blender plugin for visualizing molecular dynamics simulations using industry‐standard rendering techniques

Molecular dynamics (MD) simulations provide critical insights into many biological mechanisms. Programs such as VMD, Chimera, and PyMOL can produce impressive simulation visualizations, but they lack many advanced rendering algorithms common in the film and video‐game industries. In contrast, the modeling program Blender includes such algorithms but cannot import MD‐simulation data. MD trajectories often require many gigabytes of memory/disk space, complicating Blender import. We present Pyrite, a Blender plugin that overcomes these limitations. Pyrite allows researchers to visualize MD simulations within Blender, with full access to Blender's cutting‐edge rendering techniques. We expect Pyrite‐generated images to appeal to students and non‐specialists alike. A copy of the plugin is available at http://durrantlab.com/pyrite/ , released under the terms of the GNU General Public License Version 3. © 2017 Wiley Periodicals, Inc.     

MILCH SHAKE: An efficient method for constraint dynamics applied to alkanes

We describe a method to impose constraints in a molecular dynamics simulation. A technique developed to solve the special case of a linear topology (MILC SHAKE) is hybridized with the SHAKE algorithm. The methodology, which we term MILC‐hybridized SHAKE (or MILCH SHAKE), applies to more complex topologies. Here we consider the important case of all atom models of alkanes. Exploiting the mass difference between carbon and hydrogen we show that for higher alkanes MILCH SHAKE can be an order of magnitude faster than SHAKE. © 2009 Wiley Periodicals, Inc. J Comput Chem, 2009     

Bead-spring models of entangled polymer melts: Comparison of hard-core and soft-core potentials

Two bead-spring models of flexible chains for generic coarse graining of entangled polymer melts, the excluded volume Kremer–Grest (KG) model and the modified segmental repulsive potential (mSRP) combined with a weakly repulsive potential, are compared. For chains containing an equivalent number of entanglements, we compare the chain characteristics of the KG and mSRP polymer models by determining the ratios of the entanglement lengths , the required total number of particles to capture comparable entanglement phenomena , and the time scaling ratios τ^mSRP/τ^KG. Our findings show that systems using the mSRP polymer model require half the number of particles and relax four times faster compared to the KG polymer model. © 2012 Wiley Periodicals, Inc. J Polym Sci Part B: Polym Phys, 2012     

Structure and Thermodynamics of Mg:Phosphate Interactions in Water: A Simulation Study

The association of Mg²⁺ and H₂PO₄^? in water can give insights into Mg:phosphate interactions in general, which are very widespread, but for which experimental data is surprisingly sparse. It is studied through molecular dynamics simulations (>100 ns) by using the polarizable AMOEBA force field, and the association free energy is computed for the first time. Explicit consideration of outer‐sphere and two types of inner‐sphere association provides considerable insight into the dynamics and thermodynamics of ion pairing. After careful assessment of the computational approximations, the agreement with experimental values indicates that the methodology can be extended to other inorganic and biological Mg:phosphate interactions in solution.     

Non-iterative and exact method for constraining particles in a linear geometry

We present a practical numerical method for evaluating the Lagrange multipliers necessary for maintaining a constrained linear geometry of particles in dynamical simulations. The method involves no iterations and is limited in accuracy only by the numerical methods for solving small systems of linear equations. As a result of the non-iterative and exact (within numerical accuracy) nature of the procedure, there is no drift in the constrained geometry, and the method is therefore readily applied to molecular dynamics simulations of, for example, rigid linear molecules or materials of non-spherical grains. We illustrate the approach through implementation in the commonly used second-order velocity-explicit Verlet method. © 2005 Wiley Periodicals, Inc. J Polym Sci Part B: Polym Phys 43: 911-916, 2005     

Molecular Dynamics Simulations in Designing DARPins as Phosphorylation-Specific Protein Binders of ERK2

Extracellular signal-regulated kinases 1 and 2 (ERK1/2) play key roles in promoting cell survival and proliferation through the phosphorylation of various substrates. Remarkable antitumour activity is found in many inhibitors that act upstream of the ERK pathway. However, drug-resistant tumour cells invariably emerge after their use due to the reactivation of ERK1/2 signalling. ERK1/2 inhibitors have shown clinical efficacy as a therapeutic strategy for the treatment of tumours with mitogen-activated protein kinase (MAPK) upstream target mutations. These inhibitors may be used as a possible strategy to overcome acquired resistance to MAPK inhibitors. Here, we report a class of repeat proteins—designed ankyrin repeat protein (DARPin) macromolecules targeting ERK2 as inhibitors. The structural basis of ERK2–DARPin interactions based on molecular dynamics (MD) simulations was studied. The information was then used to predict stabilizing mutations employing a web-based algorithm, MAESTRO. To evaluate whether these design strategies were successfully deployed, we performed all-atom, explicit-solvent molecular dynamics (MD) simulations. Two mutations, Ala → Asp and Ser → Leu, were found to perform better than the original sequence (DARPin E40) based on the associated energy and key residues involved in protein-protein interaction. MD simulations and analysis of the data obtained on these mutations supported our predictions.     

A Method to Explore Protein Side Chain Conformational Variability Using Experimental Data

Experimentally measured values of molecular properties or observables of biomolecules such as proteins are generally averages over time and space, which do not contain su?cient information to determine the underlying conformational distribution of the molecules in solution. The relationship between experimentally measured NMR ³J‐coupling values and the corresponding dihedral angle values is a particularly complicated case due to its nonlinear, multiple‐valued nature. Molecular dynamics (MD) simulations at constant temperature can generate Boltzmann ensembles of molecular structures that are free from a priori assumptions about the nature of the underlying conformational distribution. They suffer, however, from limited sampling with respect to time and conformational space. Moreover, the quality of the obtained structures is dependent on the choice of force ?eld and solvation model. A recently proposed method that uses time‐averaging with local‐elevation (LE) biasing of the conformational search provides an elegant means of overcoming these three problems. Using a set of side chain ³J‐coupling values for the FK506 binding protein (FKBP), we ?rst investigate the uncertainty in the angle values predicted theoretically. We then propose a simple MD‐based technique to detect inconsistencies within an experimental data set and identify degrees of freedom for which conformational averaging takes place or for which force ?eld parameters may be de?cient. Finally, we show that LE MD is the best method for producing ensembles of structures that, on average, ?t the experimental data.     

Properties of Polyvinyl Alcohol Oligomers: A Molecular Dynamics Study

MD studies of liquid isopropyl alcohol and melts of short poly(vinyl alcohol) (PVA) oligomers are described. The specific volume was found to depend inversely on the number N of repeat units. If the chain length is enhanced, the viscosity of the PVA melt increases and the peaks in the radial distribution function become sharper. Additional peaks that appear in melts of PVA chains are of pure intramolecular origin. The calculated radius of gyration was found to depend on the number of formula units via . The orientation correlation functions showed that all molecular vectors of PVA melts with chain lengths N = 1, 2, 3 relax completely within a few nanoseconds. The relaxation times for the O H bond vector as obtained via the Kohlrausch‐Williams‐Watts expression showed an exponential dependence on the number of repeat units.

     

Approaching Dissolved Species in Ammonoacidic GaN Crystal Growth: A Combined Solution NMR and Computational Study

Solutions of gallium trihalides GaX₃ (X=F, Cl, Br, I) and their ammoniates in liquid ammonia were studied at ambient temperature under autogenous pressure by multinuclear (⁷¹Ga, ³⁵Cl, ⁸¹Br) NMR spectroscopy. To unravel the role of pH, the analyses were done both in absence and in presence of ammonium halides, which are employed as mineralizers during ammonoacidic gallium nitride crystal growth. While gallium trifluoride and its ammoniate were found to be too sparingly soluble to give rise to a NMR signal, the spectra of solutions of the heavier halides reveal the presence of a single gallium-containing species in all cases. DFT calculations and molecular dynamics simulations suggest the identification of this species as consisting of a [Ga(NH₃)₆]³⁺ cation and up to six surrounding halide anions, resulting in an overall trend towards negative complex charge. Quantitative ⁷¹Ga NMR studies on saturated solutions of GaCl₃ containing various amounts of additional NH₄Cl revealed a near linear increase of GaCl₃ solubility with mineralizer concentration of about 0.023 mol GaCl₃ per mol NH₄Cl at room temperature. These findings reflect the importance of Coulombic shielding for the inhibition of oligomerization and precipitation processes and help to rationalize both the low solubility of gallium halides in neutral ammonia solution and, in turn, the proliferating effect of the mineralizer during ammonoacidic gallium nitride formation.