Assessing the performance of the g_mmpbsa tools to simulate the inhibition of oseltamivir to influenza virus neuraminidase by molecular mechanics Poisson–Boltzmann surface area methods

The molecular mechanics Poisson–Boltzmann surface area (MM-PBSA) method for GROMACS (g_mmpbsa) is an open-source tool that is capable of reading the trajectories generated by GROMACS and calculating the binding free energy using the MM-PBSA method. However, there are multiple force fields available for users to choose from in the GROMACS software, and there are also different solvent water models to combine with the chosen force fields. These different combinations of parameters may significantly impact the results of g_mmpbsa calculation. Unfortunately, the exact combination of force field and solvent water that can well calculate the free energy of the receptor–ligand binding in GROMACS has not been explored yet. To resolve the above issues, this study mainly explored the molecular dynamics (MD) simulations by GROMACS with the six commonly used force fields and three solvent water models, in combination with g_mmpbsa, to calculate the binding free energies of the influenza virus neuraminidase and its mutants with inhibitor oseltamivir carboxylate and compared the present results with previous published results of Amber software from ours and other researchers. Finally, we provided an optimized calculation model, as well as suggestions that may serve as advice and guidance for future computer-aided designs of drug molecules.     

MkVsites: A tool for creating GROMACS virtual sites parameters to increase performance in all-atom molecular dynamics simulations

The absolute performance of any all-atom molecular dynamics simulation is typically limited by the length of the individual timesteps taken when integrating the equations of motion. In the GROMACS simulation software, it has for a long time been possible to use so-called virtual sites to increase the length of the timestep, resulting in a large gain of simulation efficiency. Up until now, support for this approach has in practice been limited to the standard 20 amino acids however, shrinking the applicability domain of virtual sites. MkVsites is a set of python tools which provides a convenient way to obtain all parameters necessary to use virtual sites for virtually any molecules in a simulation. Required as input to MkVsites is the molecular topology of the molecule(s) in question, along with a specification of where to find the parent force field. As such, MkVsites can be a very valuable tool suite for anyone who is routinely using GROMACS for the simulation of molecular systems.     

Conformational analysis of hydroxymatairesinol in aqueous solution with molecular dynamics

Molecular dynamics simulations were performed on the naturally occuring lignan hydroxymatairesinol (HMR) using the GROMACS software. The aim of this study was to explore the conformational behavior of HMR in aqueous solution adopting the TIP4P model. The topology of HMR was constructed by hand and HMR was modeled with the OPLS‐AA force field implemented in GROMACS. The five torsional angles in HMR were properly analyzed during the simulations. Correlations through certain patterns were observed between the angles. The determining property for the conformation preferred in aqueous solution was found to be the dipole moment and not the lowest energy in gas phase. The solvation effects on HMR was also studied by quantum chemical calculations applying the COnductorlike Screening MOdel (COSMO), the results of which were compared with results from a previous study using the Polarized Continuum Model (PCM). In the present work, COSMO was found to give more credible relative energies than PCM. © 2009 Wiley Periodicals, Inc., J Comput Chem, 2009     

Molecular dynamics simulation of nonsteroidal antiinflammatory drugs,naproxen and relafen,in a lipid bilayer membrane

Naproxen and relafen, as nonsteroidal antiinflammatory drugs, were simulated in neutral and charged forms and their effects on a lipid bilayer membrane were investigated by molecular dynamics simulation using Groningen machine for chemical simulations software (GROMACS). Simulation of 10 systems was performed, which included different dosages of the drug molecules, naproxen and Relafen, in charged and neutral forms, and a mixture of naproxen and Relafen in neutral forms. The effects of the mixture and the individual drugs' dosages on membrane properties, such as electrostatic potential, order parameter, diffusion coefficients, and hydrogen bond formation, were analyzed. Hydration of the drugs in the membrane system was investigated using radial distribution function analysis. Using fully hydrated dimyristoylphosphatidylcholine (DMPC) as a reference system, 128 lipid molecules and water molecules were simulated exclusively, and the same simulation technique was performed on 10 other systems, including drug mixtures and a DMPC membrane. Angular distributions of lipid chains of the membrane were calculated, and the effects of the drug insertion and chain orientation in the membrane were evaluated. © 2013 Wiley Periodicals, Inc.     

Best bang for your buck: GPU nodes for GROMACS biomolecular simulations

The molecular dynamics simulation package GROMACS runs efficiently on a wide variety of hardware from commodity workstations to high performance computing clusters. Hardware features are well‐exploited with a combination of single instruction multiple data, multithreading, and message passing interface (MPI)‐based single program multiple data/multiple program multiple data parallelism while graphics processing units (GPUs) can be used as accelerators to compute interactions off‐loaded from the CPU. Here, we evaluate which hardware produces trajectories with GROMACS 4.6 or 5.0 in the most economical way. We have assembled and benchmarked compute nodes with various CPU/GPU combinations to identify optimal compositions in terms of raw trajectory production rate, performance‐to‐price ratio, energy efficiency, and several other criteria. Although hardware prices are naturally subject to trends and fluctuations, general tendencies are clearly visible. Adding any type of GPU significantly boosts a node's simulation performance. For inexpensive consumer‐class GPUs this improvement equally reflects in the performance‐to‐price ratio. Although memory issues in consumer‐class GPUs could pass unnoticed as these cards do not support error checking and correction memory, unreliable GPUs can be sorted out with memory checking tools. Apart from the obvious determinants for cost‐efficiency like hardware expenses and raw performance, the energy consumption of a node is a major cost factor. Over the typical hardware lifetime until replacement of a few years, the costs for electrical power and cooling can become larger than the costs of the hardware itself. Taking that into account, nodes with a well‐balanced ratio of CPU and consumer‐class GPU resources produce the maximum amount of GROMACS trajectory over their lifetime. © 2015 The Authors. Journal of Computational Chemistry Published by Wiley Periodicals, Inc.     

The GROMOS software for biomolecular simulation: GROMOS05

We present the latest version of the Groningen Molecular Simulation program package, GROMOS05. It has been developed for the dynamical modelling of (bio)molecules using the methods of molecular dynamics, stochastic dynamics, and energy minimization. An overview of GROMOS05 is given, highlighting features not present in the last major release, GROMOS96. The organization of the program package is outlined and the included analysis package GROMOS++ is described. Finally, some applications illustrating the various available functionalities are presented.     

Flooding in GROMACS: accelerated barrier crossings in molecular dynamics

The major bottleneck of today's atomistic molecular dynamics (MD) simulations is that because of the enormous computational effort involved, only processes at nanoseconds to microseconds time scales or faster can be studied directly. Unfortunately, apart from a few exceptions, relevant processes, such as chemical reactions or many large scale conformational transitions in proteins, occur at slower time scales and therefore are currently far out of reach for conventional MD. The flooding technique addresses this problem by inclusion of a flooding potential into the force field. This flooding potential locally destabilizes the educt state and thereby significantly accelerates the escape from the initial energy well without affecting the reaction pathway. Here, we summarize the theory and method for the computational chemistry community and detail the implementation within the official version 3.3 of the freely available MD program package GROMACS. Two examples shall demonstrate the application of flooding to accelerate conformational transitions and chemical reactions. The second example was carried out within a QM/MM framework.     

GridMAT‐MD: A grid‐based membrane analysis tool for use with molecular dynamics

GridMAT‐MD is a new program developed to aid in the analysis of lipid bilayers from molecular dynamics simulations. It reads a GROMACS coordinate file and generates two types of data: a two‐dimensional contour plot depicting membrane thickness, and a polygon‐based tessellation of the individual lipid headgroups. GridMAT‐MD can also account for proteins or small molecules within the headgroups of the lipids, closely approximating their occupied lateral area. The program requires no installation, is fast, and is freely available. © 2008 Wiley Periodicals, Inc. J Comput Chem, 2009     

Hybrid particle‐field molecular dynamics simulations: Parallelization and benchmarks

The parallel implementation of a recently developed hybrid scheme for molecular dynamics (MD) simulations (Milano and Kawakatsu, J Chem Phys 2009, 130, 214106) where self‐consistent field theory (SCF) and particle models are combined is described. Because of the peculiar formulation of the hybrid method, considering single particles interacting with density fields, the most computationally expensive part of the hybrid particle‐field MD simulation can be efficiently parallelized using a straightforward particle decomposition algorithm. Benchmarks of simulations, including comparisons of serial MD and MD‐SCF program profiles, serial MD‐SCF and parallel MD‐SCF program profiles, and parallel benchmarks compared with efficient MD program GROMACS 4.5.4 are tested and reported. The results of benchmarks indicate that the proposed parallelization scheme is very efficient and opens the way to molecular simulations of large scale systems with reasonable computational costs. © 2012 Wiley Periodicals, Inc.     

Development of the force field parameters for phosphoimidazole and phosphohistidine

Phosphorylation of histidine-containing proteins is a key step in the mechanism of many phosphate transfer enzymes (kinases, phosphatases) and is the first stage in a wide variety of signal transduction cascades in bacteria, yeast, higher plants, and mammals. Studies of structural and dynamical aspects of such enzymes in the phosphorylated intermediate states are important for understanding the intimate molecular mechanisms of their functioning. Such information may be obtained via molecular dynamics and/or docking simulations, but in this case appropriate force field parameters for phosphohistidine should be explicitly defined. In the present article we describe development of the GROMOS96 force field parameters for phosphoimidazole molecule--a realistic model of the phosphohistidine side chain. The parameterization is based on the results of ab initio quantum chemical calculations with subsequent refinement and testing using molecular mechanics and molecular dynamics simulations. The set of force constants and equilibrium geometry is employed to derive force field for the phosphohistidine moiety. Resulting parameters and topology are incorporated into the molecular modeling package GROMACS and used in molecular dynamics simulations of a phosphohistidine-containing protein in explicit solvent.     

OBGMX: A web‐based generator of GROMACS topologies for molecular and periodic systems using the universal force field

OBGMX is a web service providing topologies for the GROMACS molecular dynamics software package according to the Universal Force Field, as implemented in the Open Babel package. OBGMX can deal with molecular and periodic systems. The geometrical parameters appearing in the potential energy functions for the bonded interactions can be set to those measured in the input configuration. The performance of OBGMX in reproducing the structure of periodic systems is analyzed by calculating the root mean‐squared displacements of optimized configurations of a large set of metal–organic frameworks. OBGMX is available at http://software‐lisc.fbk.eu/obgmx/ . © 2012 Wiley Periodicals, Inc.     

Implementation of extended Lagrangian dynamics in GROMACS for polarizable simulations using the classical Drude oscillator model

Explicit treatment of electronic polarization in empirical force fields used for molecular dynamics simulations represents an important advancement in simulation methodology. A straightforward means of treating electronic polarization in these simulations is the inclusion of Drude oscillators, which are auxiliary, charge‐carrying particles bonded to the cores of atoms in the system. The additional degrees of freedom make these simulations more computationally expensive relative to simulations using traditional fixed‐charge (additive) force fields. Thus, efficient tools are needed for conducting these simulations. Here, we present the implementation of highly scalable algorithms in the GROMACS simulation package that allow for the simulation of polarizable systems using extended Lagrangian dynamics with a dual Nosé–Hoover thermostat as well as simulations using a full self‐consistent field treatment of polarization. The performance of systems of varying size is evaluated, showing that the present code parallelizes efficiently and is the fastest implementation of the extended Lagrangian methods currently available for simulations using the Drude polarizable force field.     

Performance evaluation of the zero‐multipole summation method in modern molecular dynamics software

The zero‐multiple summation method (ZMM) is a cutoff‐based method for calculating electrostatic interactions in molecular dynamics simulations, utilizing an electrostatic neutralization principle as a physical basis. Since the accuracies of the ZMM have been revealed to be sufficient in previous studies, it is highly desirable to clarify its practical performance. In this paper, the performance of the ZMM is compared with that of the smooth particle mesh Ewald method (SPME), where the both methods are implemented in molecular dynamics software package GROMACS. Extensive performance comparisons against a highly optimized, parameter‐tuned SPME implementation are performed for various‐sized water systems and two protein–water systems. We analyze in detail the dependence of the performance on the potential parameters and the number of CPU cores. Even though the ZMM uses a larger cutoff distance than the SPME does, the performance of the ZMM is comparable to or better than that of the SPME. This is because the ZMM does not require a time‐consuming electrostatic convolution and because the ZMM gains short neighbor‐list distances due to the smooth damping feature of the pairwise potential function near the cutoff length. We found, in particular, that the ZMM with quadrupole or octupole cancellation and no damping factor is an excellent candidate for the fast calculation of electrostatic interactions. © 2018 Wiley Periodicals, Inc.     

RedMD—Reduced molecular dynamics package

We developed a software package (RedMD) to perform molecular dynamics simulations and normal mode analysis of reduced models of proteins, nucleic acids, and their complexes. With RedMD one can perform molecular dynamics simulations in a microcanonical ensemble, with Berendsen and Langevin thermostats, and with Brownian dynamics. We provide force field and topology generators which are based on the one‐bead per residue/nucleotide elastic network model and its extensions. The user can change the force field parameters with the command line options that are passed to generators. Also, the generators can be modified, for example, to add new potential energy functions. Normal mode analysis tool is available for elastic or anisotropic network models. The program is written in C and C++ languages and the structure/topology of a molecule is based on an XML format. OpenMP technology for shared‐memory architectures was used for code parallelization. The code is distributed under GNU public licence and available at http://bionano.icm.edu.pl/software/ . © 2009 Wiley Periodicals, Inc. J Comput Chem, 2009     

GENESIS 1.1: A hybrid‐parallel molecular dynamics simulator with enhanced sampling algorithms on multiple computational platforms

GENeralized‐Ensemble SImulation System (GENESIS) is a software package for molecular dynamics (MD) simulation of biological systems. It is designed to extend limitations in system size and accessible time scale by adopting highly parallelized schemes and enhanced conformational sampling algorithms. In this new version, GENESIS 1.1, new functions and advanced algorithms have been added. The all‐atom and coarse‐grained potential energy functions used in AMBER and GROMACS packages now become available in addition to CHARMM energy functions. The performance of MD simulations has been greatly improved by further optimization, multiple time‐step integration, and hybrid (CPU + GPU) computing. The string method and replica‐exchange umbrella sampling with flexible collective variable choice are used for finding the minimum free‐energy pathway and obtaining free‐energy profiles for conformational changes of a macromolecule. These new features increase the usefulness and power of GENESIS for modeling and simulation in biological research. © 2017 Wiley Periodicals, Inc.     

Partition coefficients of organic molecules in squalane and water/ethanol mixtures by molecular dynamics simulations

Accurate partition coefficient data of migrants between a polymer and a solvent are of paramount importance for estimating the migration of the migrant over time, including the concentration of the migrant at infinite time in the two solvents. In this article it is shown how this partition coefficient can be estimated for both a small hydrophilic and a hydrophobic organic molecules between squalane (used here to mimic low density poly ethylene) and water/ethanol solutes using thermodynamic integration to calculate the free energy of solvation. Molecular dynamics simulations are performed, using the GROMACS software, by slowly decoupling of firstly the electrostatic and then the Lennard-Jones interactions between molecules in the simulation box. These calculations depend very much on the choice of force field. Two force fields have been tested in this work, the TraPPE-UA (united-atom) and the OPLS-AA (all-atom). The computational cheaper TraPPE-UA force field showed to be more accurate over the whole range of systems compared to the OPLS-AA force field. Moreover, some of the calculations were done with five different water models to investigate the influence of the specific water model on the calculations. It was found that the combination of the TraPPE-UA force field and the TIP4p water model gave the best results. Based on the methodology proposed in this article, it is possible to obtain good partition coefficients only knowing the chemical structure of the molecules in the system.     

CHARMM‐GUI ligand reader and modeler for CHARMM force field generation of small molecules

Reading ligand structures into any simulation program is often nontrivial and time consuming, especially when the force field parameters and/or structure files of the corresponding molecules are not available. To address this problem, we have developed Ligand Reader & Modeler in CHARMM‐GUI. Users can upload ligand structure information in various forms (using PDB ID, ligand ID, SMILES, MOL/MOL2/SDF file, or PDB/mmCIF file), and the uploaded structure is displayed on a sketchpad for verification and further modification. Based on the displayed structure, Ligand Reader & Modeler generates the ligand force field parameters and necessary structure files by searching for the ligand in the CHARMM force field library or using the CHARMM general force field (CGenFF). In addition, users can define chemical substitution sites and draw substituents in each site on the sketchpad to generate a set of combinatorial structure files and corresponding force field parameters for throughput or alchemical free energy simulations. Finally, the output from Ligand Reader & Modeler can be used in other CHARMM‐GUI modules to build a protein‐ligand simulation system for all supported simulation programs, such as CHARMM, NAMD, GROMACS, AMBER, GENESIS, LAMMPS, Desmond, OpenMM, and CHARMM/OpenMM. Ligand Reader & Modeler is available as a functional module of CHARMM‐GUI at http://www.charmm-gui.org/input/ligandrm . © 2017 Wiley Periodicals, Inc.     

Interfacing the GROMOS (bio)molecular simulation software to quantum‐chemical program packages

The newly implemented quantum‐chemical/molecular‐mechanical (QM/MM) functionality of the Groningen molecular simulation (GROMOS) software for (bio)molecular simulation is described. The implementation scheme is based on direct coupling of the GROMOS C++ software to executables of the quantum‐chemical program packages MNDO and TURBOMOLE, allowing for an independent further development of these packages. The new functions are validated for different test systems using program and model testing techniques. The effect of truncating the QM/MM electrostatic interactions at various QM/MM cutoff radii is discussed and the application of semiempirical versus density‐functional Hamiltonians for a solute molecule in aqueous solution is compared. © 2012 Wiley Periodicals, Inc.