This article reports on the calibration and validation of a new GROMOS-compatible parameter set 2016H66 for small organic molecules in the condensed phase. The calibration is based on 62 organic molecules spanning the chemical functions alcohol, ether, aldehyde, ketone, carboxylic acid, ester, amine, amide, thiol, sulfide, and disulfide, as well as aromatic compounds and nucleic-acid bases. For 57 organic compounds, the calibration targets are the experimental pure-liquid density ρliq and the vaporization enthalpy ΔHvap, as well as the hydration free energy ΔGwat and the solvation free energy ΔGche in cyclohexane, at atmospheric pressure and at (or close to) room temperature. The final root-mean-square deviations (RMSD) for these four quantities over the set of compounds are 32.4 kg m(-3), 3.5 kJ mol(-1), 4.1 kJ mol(-1), and 2.1 kJ mol(-1), respectively, and the corresponding average deviations (AVED) are 1.0 kg m(-3), 0.2 kJ mol(-1), 2.6 kJ mol(-1), and 1.0 kJ mol(-1), respectively. For the five nucleic-acid bases, the parametrization is performed by transferring the final 2016H66 parameters from analogous organic compounds followed by a slight readjustment of the charges to reproduce the experimental water-to-chloroform transfer free energies ΔGtrn. The final RMSD for this quantity over the five bases is 1.7 kJ mol(-1), and the corresponding AVED is 0.8 kJ mol(-1). As an initial validation of the 2016H66 set, seven additional thermodynamic, transport, and dielectric properties are calculated for the 57 organic compounds in the liquid phase. The agreement with experiment in terms of these additional properties is found to be reasonable, with significant deviations typically affecting either a specific chemical function or a specific molecule. This suggests that in most cases, a classical force-field description along with a careful parametrization against ρliq, ΔHvap, ΔGwat, and ΔGche results in a model that appropriately describes the liquid in terms of a wide spectrum of its physical properties.

GROMOS++ is a set of C++ programs for pre- and postprocessing of molecular dynamics simulation trajectories and as such is part of the GROningen MOlecular Simulation software for (bio)molecular simulation. It contains more than 70 programs that can be used to prepare data for the production of molecular simulation trajectories and to analyze these. These programs are reviewed and the various structural, dynamic, and thermodynamic quantities that can be analyzed using time series, correlation functions, and distributions are described together with technical aspects of their implementation in GROMOS. A few examples of the use of GROMOS++ for the analysis of MD trajectories are given. A full list of all GROMOS++ programs, together with an indication of their capabilities, is given in the Appendix .

A new parameter set (53A6OXY) is developed for the GROMOS force field, that combines reoptimized parameters for the oxygen-containing chemical functions (alcohols, ethers, aldehydes, ketones, carboxylic acids, and esters) with the current biomolecular force field version (53A6) for all other functions. In the context of oxygen-containing functions, the 53A6OXY parameter set is obtained by optimization of simulated pure-liquid properties, namely the density ρliq and enthalpy of vaporization ΔHvap, as well as solvation properties, namely the free energies of solvation in water ΔGwat and in cyclohexane ΔGche, against experimental data for 10 selected organic compounds, and further tested for 25 other compounds. The simultaneous refinement of atomic charges and Lennard-Jones interaction parameters against the four mentioned types of properties provides a single parameter set for the simulation of both liquid and biomolecular systems. Small changes in the covalent parameters controlling the geometry of the oxygen-containing chemical functions are also undertaken. The new 53A6OXY force-field parameters reproduce the mentioned experimental data within root-mean-square deviations of 22.4 kg m(-3) (ρliq), 3.1 kJ mol(-1) (ΔHvap), 3.0 kJ mol(-1) (ΔGwat), and 1.7 kJ mol(-1) (ΔGche) for the 35 compounds considered.

An extension 53A6 OXY+D to the GROMOS 53A6 OXY force field is reported that includes an accurate description of the vicinal diether function. The calibration is based on the model compound 1,2-dimethoxyethane (DXE) and involves a fitting of the relevant torsional-energy parameters against quantum-mechanical (QM) rotational energy profiles for the OCCO and CCOC dihedral angles in vacuum, followed by a validation against experimental conformer populations in the pure liquid and in aqueous mixtures. A systematic comparison between the 53A6, 56A6 CARBO , 53A6 OXY , and 53A6 OXY+D parameter sets is also performed in terms of these properties, as well as in terms of the thermodynamic properties of dimethylether (DME), diethylether (DEE), 1-methoxypropane (MPH), and DXE. Finally, the new parameter set is further validated in the context of polyethers, namely polyethyleneoxide (PEO) and polyethylenegycol (PEG). The 53A6 OXY+D set reproduces well the QM rotational profiles of DXE in vacuum (by calibration), the conformational populations of DXE in the pure liquid and in aqueous mixtures, and the experimental thermodynamic pure-liquid and (polar and nonpolar) solvation properties of DME, DEE, MPH, and DXE. In particular, it accounts appropriately for the gauche-effect, both in its solvent-independent stereoelectronic component and in its solvent-dependent dielectric-screening component. In contrast to 53A6 OXY , it also suggests a higher affinity of DXE for water compared to octanol, in agreement with the experimental partition coefficient. In the context of aqueous polyethers, the calculated size (Flory) exponent (ν g = 0.61) for the molecular-weight dependence of the radius of gyration and persistence length (L p = 0.39 ± 0.04 nm) agree well with estimates based on experiment or previous simulations with other force fields. The simulations also suggest a picture of aqueous polyethers as "water sponges", in which the diether function "adsorbs" an essentially constant number of water molecules corresponding to first-shell hydrogen-bonded saturation of its oxygen atoms, with a tendency to include other ether oxygen atoms along the chain in the second shell, resulting in "water bridging".

Since the most recent description of the functionalities of the GROMOS software for biomolecular simulation in 2005 many new functions have been implemented. In this article, the new functionalities that involve modified forces in a molecular dynamics (MD) simulation are described: the treatment of electronic polarizability, an implicit surface area and internal volume solvation term to calculate interatomic forces, functions for the GROMOS coarse-grained supramolecular force field, a multiplicative switching function for nonbonded interactions, adiabatic decoupling of a number of degrees of freedom with temperature or force scaling to enhance sampling, and nonequilibrium MD to calculate the dielectric permittivity or viscosity. Examples that illustrate the use of these functionalities are given.

Direct optimization against experimental condensedphase properties concerning small organic molecules still represents the most reliable way to calibrate the empirical parameters of a force field. However, compared to a corresponding calibration against quantum-mechanical (QM) calculations concerning isolated molecules, this approach is typically very tedious and time-consuming. The present article describes an integrated scheme for the automated refinement of force-field parameters against experimental condensedphase data, considering entire classes of organic molecules constructed using a fragment library via combinatorial isomer enumeration. The main steps of the scheme, referred to as CombiFF, are as follows: (i) definition of a molecule family; (ii) combinatorial enumeration of all isomers; (iii) query for experimental data; (iv) automatic construction of the molecular topologies by fragment assembly; and (v) iterative refinement of the force-field parameters considering the entire family. As a first application, CombiFF is used here to design a GROMOS-compatible united-atom force field for the saturated acyclic haloalkane family. This force field relies on an electronegativity-equalization scheme for the atomic partial charges and involves no specific terms for σ-holes and halogen bonding. A total of 749 experimental liquid densities ρ liq and vaporization enthalpies ΔH vap concerning 486 haloalkanes are considered for calibration and validation. The resulting root-mean-square deviations from experiment are 49.8 (27.6) kg•m −3 for ρ liq and 2.7 (1.8) kJ•mol −1 for ΔH vap for the calibration (validation) set. The values are lower for the validation set which contains larger molecules (stronger influence of purely aliphatic interactions). The trends in the optimized parameters along the halogen series and across the compound family are in line with chemical intuition based on considerations related to size, polarizability, softness, electronegativity, induction, and hyperconjugation. This observation is particularly remarkable considering that the force-field calibration did not involve any QM calculation. Once the time-consuming task of target-data selection/curation has been performed, the optimization of a force field only takes a few days. As a result, CombiFF enables an easy assessment of the consequences of functional-form decisions on the accuracy of a force field at an optimal level of parametrization.

A mecânica molecular é amplamente usada na simulação de biomoléculas. Um arquivo de topologia molecular contendo todos os tipos de átomos, que dependem do ambiente químico, tem de ser construído. MKTOP é um software gratuito capaz de construir topologias moleculares para o GROMACS, sendo assim uma ferramenta útil para seus usuários.Molecular mechanics methods are widely-used for simulations of biomolecules. A molecular topology file containing all atom types, which depend on the chemical environment, must be constructed. MKTOP is a free-software capable of automatic atom type recognition and construction of molecular topologies for GROMACS, being a useful tool for its users. Keywords: molecular mechanics, atom-type recognition, molecular topology, GROMACS, OPLS IntroductionThe use of molecular mechanics (MM) methods in the treatment of biomolecular systems has been increasing steadily. These methods use empirical force fields to calculate interactions between atoms. Applications range from simple geometry optimizations to estimations of binding affinity, molecular dynamics (MD) simulations, among others. GROMACS 1 is one of the most utilized MD software packages and it has the advantage of being free software, distributed under the GNU license. It is able to perform calculations with several force fields, one of them being OPLS-AA.2 This combination is widely-used in protein simulations.In order to set up a MM calculation, one must generate a topology file for the system, in which the connectivities between the atoms and the atom type, which is determined by the concept of chemical function, are specified.Chemical function determination is the major problem to address when creating a topology. Most molecular mechanics softwares have routines for generating a topology, but these are usually only effective for peptides. Although the systems of main interest in the field are proteins, possible inhibitors, co-factors, substrates and agonists may not be peptides. Therefore, automatic routines which successfully identify atom types are extremely helpful to the user. One such routine is called PRODRG 3 , but it is only able to create topologies for united-atom force fields. More recently, a routine named antechamber, 4 capable of creating all-atom molecular topologies, has been included in the last AMBER 5 distribution. However, AMBER is not freely available. Therefore, a program capable of building topologies for GROMACS would be of great appeal.In this paper we report the development of an automatic routine, named MKTOP, to create molecular topologies for GROMACS, utilizing the OPLS-AA force-field. Computational MethodsMKTOP is a user-friendly computational routine written in Perl. A single command line is required to generate a molecular topology. How MKTOP worksThe starting point for constructing a topology is, obviously, a list of the coordinates of all the atoms present in the system; these must be provided to MKTOP in a PDB format file. The atomic charges, which are essential to perform a MM calculation, may be ...

Explicit-solvent molecular dynamics (MD) simulations of the monoglyceride glycerol-1-monopalmitin (GMP; bilayer patch of 2 × 6 × 6 lipids) at different hydration levels (full, half, or quarter hydration) and at different temperatures (318 to 338 K) are reported. The 40 ns simulations (some extended to 200 ns) are initiated from structures appropriate for the gel (GL) or liquid-crystal (LC) phases, with the goal of investigating whether atomistic MD simulations on this time scale can be used to monitor GL ↔ LC transitions in lipid bilayers, and to evaluate the corresponding transition temperatures Tm (as well as the influence of hydration on Tm) in a reliable fashion. The main conclusions are as follows: (i) The GL → LC transition of GMP can be observed on the 40 ns time scale. (ii) The LC → GL transition is comparatively slower, requiring simulations on the 200 ns time scale. (iii) A set of simulations initiated from a structure appropriate for the GL phase and carried out at slightly different temperatures permits the determination of a reliable value for Tm. (iv) The calculated Tm values reproduce the experimentally observed increase in this transition temperature upon decreasing the bilayer hydration. (v) The Tm values calculated at the three hydration levels considered are in essentially quantitative agreement with the experimental phase diagram of GMP. To our knowledge, this study represents the first accurate determination of the Tm of a lipid via atomistic simulations of the (reversible) GL ↔ LC phase transition, as well as the first direct simulation evidence for the increase in the transition temperature upon dehydration. The possible direct determination of Tm and the characterization of environmental effects on this quantity by simulation opens up promising perspectives in the contexts of force field refinement and the investigation of dehydration-induced damages in living cells (and bioprotection by cosolutes).