An improved OPLS-AA force field for carbohydrates

This work describes an improved version of the original OPLS-all atom (OPLS-AA) force field for carbohydrates (Damm et al., J Comp Chem 1997, 18, 1955). The improvement is achieved by applying additional scaling factors for the electrostatic interactions between 1,5- and 1,6-interactions. This new model is tested first for improving the conformational energetics of 1,2-ethanediol, the smallest polyol. With a 1,5-scaling factor of 1.25 the force field calculated relative energies are in excellent agreement with the ab initio-derived data. Applying the new 1,5-scaling makes it also necessary to use a 1,6-scaling factor for the interactions between the C4 and C6 atoms in hexopyranoses. After torsional parameter fitting, this improves the conformational energetics in comparison to the OPLS-AA force field. The set of hexopyranoses included in the torsional parameter derivation consists of the two anomers of D-glucose, D-mannose, and D-galactose, as well as of the methyl-pyranosides of D-glucose, D-mannose. Rotational profiles for the rotation of the exocyclic group and of different hydroxyl groups are also compared for the two force fields and at the ab initio level of theory. The new force field reduces the overly high barriers calculated using the OPLS-AA force field. This leads to better sampling, which was shown to produce more realistic conformational behavior for hexopyranoses in liquid simulation. From 10-ns molecular dynamics (MD) simulations of alpha-D-glucose and alpha-D-galactose the ratios for the three different conformations of the hydroxymethylene group and the average (3)J(H,H) coupling constants are derived and compared to experimental values. The results obtained for OPLS-AA-SEI force field are in good agreement with experiment whereas the properties derived for the OPLS-AA force field suffer from sampling problems. The undertaken investigations show that the newly derived OPLS-AA-SEI force field will allow simulating larger carbohydrates or polysaccharides with improved sampling of the hydroxyl groups.     

Parameterization of OPLS-AA force field for the conformational analysis of macrocyclic polyketides

The parameters for the OPLS-AA potential energy function have been extended to include some functional groups that are present in macrocyclic polyketides. Existing OPLS-AA torsional parameters for alkanes, alcohols, ethers, hemiacetals, esters, and ketoamides were improved based on MP2/aug-cc-pVTZ and MP2/aug-cc-pVDZ calculations. Nonbonded parameters for the sp(3) carbon and oxygen atoms were refined using Monte Carlo simulations of bulk liquids. The resulting force field predicts conformer energies and torsional barriers of alkanes, alcohols, ethers, and hemiacetals with an overall RMS deviation of 0.40 kcal/mol as compared to reference data. Densities of 19 bulk liquids are predicted with an average error of 1.1%, and heats of vaporization are reproduced within 2.4% of experimental values. The force field was used to perform conformational analysis of smaller analogs of the macrocyclic polyketide drug FK506. Structures that adopted low-energy conformations similar to that of bound FK506 were identified. The results show that a linker of four ketide units constitutes the shortest effector domain that allows binding of the ketide drugs to FKBP proteins. It is proposed that the exact chemical makeup of the effector domain has little influence on the conformational preference of tetraketides.     

Parametrization of macrolide antibiotics using the force field toolkit

Macrolides are an important class of antibiotics that target the bacterial ribosome. Computer simulations of macrolides are limited as specific force field parameters have not been previously developed for them. Here, we determine CHARMM‐compatible force field parameters for erythromycin, azithromycin, and telithromycin, using the force field toolkit (ffTK) plugin in VMD. Because of their large size, novel approaches for parametrizing them had to be developed. Two methods for determining partial atomic charges, from interactions with TIP3P water and from the electrostatic potential, as well as several approaches for fitting the dihedral parameters were tested. The performance of the different parameter sets was evaluated by molecular dynamics simulations of the macrolides in ribosome, with a distinct improvement in maintenance of key interactions observed after refinement of the initial parameters. Based on the results of the macrolide tests, recommended procedures for parametrizing very large molecules using ffTK are given. © 2015 Wiley Periodicals, Inc.     

Revised CHARMM force field parameters for iron‐containing cofactors of photosystem II

Photosystem II is a complex protein–cofactor machinery that splits water molecules into molecular oxygen, protons, and electrons. All‐atom molecular dynamics simulations have the potential to contribute to our general understanding of how photosystem II works. To perform reliable all‐atom simulations, we need accurate force field parameters for the cofactor molecules. We present here CHARMM bonded and non‐bonded parameters for the iron‐containing cofactors of photosystem II that include a six‐coordinated heme moiety coordinated by two histidine groups, and a non‐heme iron complex coordinated by bicarbonate and four histidines. The force field parameters presented here give water interaction energies and geometries in good agreement with the quantum mechanical target data. © 2017 Wiley Periodicals, Inc.     

A supervised fitting approach to force field parametrization with application to the SIBFA polarizable force field

A supervised, semiautomated approach to force field parameter fitting is described and applied to the SIBFA polarizable force field. The I‐NoLLS interactive, nonlinear least squares fitting program is used as an engine for parameter refinement while keeping parameter values within a physical range. Interactive fitting is shown to avoid many of the stability problems that frequently afflict highly correlated, nonlinear fitting problems occurring in force field parametrizations. The method is used to obtain parameters for the H₂O, formamide, and imidazole molecular fragments and their complexes with the Mg²⁺ cation. Reference data obtained from ab initio calculations using an auc‐cc‐pVTZ basis set exploit advances in modern computer hardware to provide a more accurate parametrization of SIBFA than has previously been available. © 2014 Wiley Periodicals, Inc.     

A molecular mechanics force field for biologically important sterols

A parameterization has been performed of the biologically important sterols cholesterol, ergosterol, and lanosterol for the CHARMM27 all-atom molecular mechanics force field. An automated parameterization method was used that involves fitting the potential to vibrational frequencies and eigenvectors derived from quantum-chemical calculations. The partial charges were derived by fitting point charges to quantum-chemically calculated electrostatic potentials. To model the dynamics of the hydroxyl groups of the sterols correctly, the parameter set was refined to reproduce the energy barrier for the rotation of the hydroxyl group around the carbon connected to the hydroxyl of each sterol. The frequency-matching plots show good agreement between the CHARMM and quantum chemical normal modes. The parameters are tested in a molecular dynamics simulation of the cholesterol crystal structure. The experimental geometry and cell dimensions are well reproduced. The force field derived here is also useful for simulating other sterols such as the phytosterols sigmasterol, and campesterol, and a variety of steroids.     

Ab initio parametrized MM3 force field for the metal-organic framework MOF-5

A new valence force field has been developed and validated for a particular class of coordination polymers known as nanoporous metal-organic frameworks (MOFs), introduced recently by the group of Yaghi. The experimental, structural, and spectroscopic data in combination with density functional theory calculations on several model systems were used to parametrize the bonded terms of the force field, which explicitly treats the metal-oxygen interactions as partially covalent as well as distinguishes different types of oxygens in the framework. Both the experimental crystal structure of MOF-5 and vibrational infrared spectrum are reproduced reasonably well. The proposed force field is believed to be useful in atomistic simulations of adsorption/diffusion of guest molecules inside the flexible pores of this important class of MOF materials.     

On the suitability of semiempirical calculations as sources of force field parameters

Summary The suitability of Dewar's Hamiltonians as a source of bonded force field parameters is explored from the comparison analysis between up to 270 semiempirically derived force field parameters and experimentally derived values reported in some of the most popular force fields. From the statistical analysis of the results, some general conclusions about the semiempirical parametrization are formulated.     

Development and validation of COMPASS force field parameters for molecules with aliphatic azide chains

To establish force-field-based (molecular) modeling capability that will accurately predict condensed-phase thermophysical properties for materials containing aliphatic azide chains, potential parameters for atom types unique to such chains have been developed and added to the COMPASS force field. The development effort identified the need to define four new atom types: one for each of the three azide nitrogen atoms and one for the carbon atom bonded to the azide. Calculations performed with the expanded force field yield (gas-phase) molecular structures and vibrational frequencies for hydrazoic acid, azidomethane, and the anti and gauche forms of azidoethane in good agreement with values determined experimentally and/or through computational quantum mechanics. Liquid densities calculated via molecular dynamics (MD) simulations were also in good agreement with published values for 13 of 15 training set compounds, the exceptions being hydrazoic acid and azidomethane. Of the 13 compounds whose densities are well simulated, nine have experimentally determined heats of vaporization reported in the open literature, and in all of these cases, MD simulated values for this property are in reasonable agreement with the published values. Simulations with the force field also yielded reasonable density estimates for a series of 2-azidoethanamines that have been synthesized and tested for use as hydrazine-alternative fuels.     

Update on phosphate and charged post‐translationally modified amino acid parameters in the GROMOS force field

In this study, we propose newly derived parameters for phosphate ions in the context of the GROMOS force field parameter sets. The non‐bonded parameters used up to now lead to a hydration free energy, which renders the dihydrogen phosphate ion too hydrophobic when compared to experimentally derived values, making a reparametrization of the phosphate moiety necessary. Phosphate species are of great importance in biomolecular simulations not only because of their crucial role in the backbone of nucleic acids but also as they represent one of the most important types of post‐translational modifications to protein side‐chains and are an integral part in many lipids. Our re‐parametrization of the free dihydrogen phosphate (H PO ) and three derivatives (methyl phosphate, dimethyl phosphate, and phenyl phosphate) leads, in conjunction with the previously updated charged side‐chains in the GROMOS parameter set 54A8, to new nucleic acid backbone parameters and a 54A8 version of the widely used GROMOS protein post‐translational modification parameter set. © 2017 Wiley Periodicals, Inc.     

Development and testing of a general amber force field

We describe here a general Amber force field (GAFF) for organic molecules. GAFF is designed to be compatible with existing Amber force fields for proteins and nucleic acids, and has parameters for most organic and pharmaceutical molecules that are composed of H, C, N, O, S, P, and halogens. It uses a simple functional form and a limited number of atom types, but incorporates both empirical and heuristic models to estimate force constants and partial atomic charges. The performance of GAFF in test cases is encouraging. In test I, 74 crystallographic structures were compared to GAFF minimized structures, with a root-mean-square displacement of 0.26 A, which is comparable to that of the Tripos 5.2 force field (0.25 A) and better than those of MMFF 94 and CHARMm (0.47 and 0.44 A, respectively). In test II, gas phase minimizations were performed on 22 nucleic acid base pairs, and the minimized structures and intermolecular energies were compared to MP2/6-31G* results. The RMS of displacements and relative energies were 0.25 A and 1.2 kcal/mol, respectively. These data are comparable to results from Parm99/RESP (0.16 A and 1.18 kcal/mol, respectively), which were parameterized to these base pairs. Test III looked at the relative energies of 71 conformational pairs that were used in development of the Parm99 force field. The RMS error in relative energies (compared to experiment) is about 0.5 kcal/mol. GAFF can be applied to wide range of molecules in an automatic fashion, making it suitable for rational drug design and database searching.     

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.     

Global optimization of parameters in the reactive force field ReaxFF for SiOH

We have used unbiased global optimization to fit a reactive force field to a given set of reference data. Specifically, we have employed genetic algorithms (GA) to fit ReaxFF to SiOH data, using an in‐house GA code that is parallelized across reference data items via the message‐passing interface (MPI). Details of GA tuning turn‐ed out to be far less important for global optimization efficiency than using suitable ranges within which the parameters are varied. To establish these ranges, either prior knowledge can be used or successive stages of GA optimizations, each building upon the best parameter vectors and ranges found in the previous stage. We have finally arrive‐ed at optimized force fields with smaller error measures than those published previously. Hence, this optimization approach will contribute to converting force‐field fitting from a specialist task to an everyday commodity, even for the more difficult case of reactive force fields. © 2013 Wiley Periodicals, Inc.     

Automatic molecular structure perception for the universal force field

The Universal Force Field (UFF) is a classical force field applicable to almost all atom types of the periodic table. Such a flexibility makes this force field a potential good candidate for simulations involving a large spectrum of systems and, indeed, UFF has been applied to various families of molecules. Unfortunately, initializing UFF, that is, performing molecular structure perception to determine which parameters should be used to compute the UFF energy and forces, appears to be a difficult problem. Although many perception methods exist, they mostly focus on organic molecules, and are thus not well‐adapted to the diversity of systems potentially considered with UFF. In this article, we propose an automatic perception method for initializing UFF that includes the identification of the system's connectivity, the assignment of bond orders as well as UFF atom types. This perception scheme is proposed as a self‐contained UFF implementation integrated in a new module for the SAMSON software platform for computational nanoscience ( http://www.samson-connect.net ). We validate both the automatic perception method and the UFF implementation on a series of benchmarks.     

Detailed considerations for a balanced and broadly applicable force field: a study of substituted benzenes modeled with OPLS-AA

Modern classical force fields have been traditionally parameterized by attempting to maximize agreement to any number of experimental and/or quantum mechanical target properties. As these force fields are pushed towards obtaining quantitative estimates of often subtle energetic differences, stringent and consistent parameterization criteria, particularly in regard to charge distributions, are required to ensure that systematic errors cancel, that parameters are transferable between molecules, and that performance does not significantly deteriorate when using more approximate methods, such as with continuum solvent models. Relative free energies of hydration are presented here for 40 mono- and disubstituted benzenes modeled with the OPLS-AA force field; heats of vaporization and pure liquid densities at standard conditions are presented when experimental data is available. Overall agreement between OPLS-AA and experiment is remarkable (average error = 0.5 kcal/mol for DeltaDeltaG(hydration), 1.0 kcal/mol for DeltaH(vap) (0), 0.02 g/mL for densities), yet several functional groups are identified as having consistent and correctable errors (alkyl-, nitro-, and thiobenzenes). Relative free energies of hydration obtained with rigorous free energy perturbations using explicit solvent are also compared with energies from minimizations using a generalized Born model (GB). There is high correlation between these estimates (R = 0.99), and as demonstrated here, reparameterization of the aforementioned groups can be guided with rapid GB calculations.     

CH/pi interactions involving aromatic amino acids: refinement of the CHARMM tryptophan force field

High-level ab initio calculations have been carried out to study weak CH/pi interactions and as a check of the CHARMM force field for aromatic amino acids. Comparisons with published data indicate that the MP2/cc-pVTZ level of theory is suitable for calculations of CH/pi interaction, including the T-shape benzene dimer. This level of theory was, therefore, applied to investigate CH/pi interactions between ethene or cis-2-butene and benzene in a variety of orientations. In addition, complexes between ethene and a series of model compounds (toluene, methylindole and p-cresol) representing the aromatic amino acids were studied motivated by the presence of CH/pi interactions in biological systems. Ab initio binding energies were compared to the binding energies obtained with the CHARMM22 force field. In the majority of orientations, CHARMM22 reproduces the preferred binding modes, with excellent agreement for the benzene dimer. Small discrepancies found in the calculations involving methylindole along with a survey of published thermodynamic data for the aromatic amino acids prompted additional optimization of the tryptophan force field. Partial atomic charges, Lennard-Jones parameters, and force constants were improved to obtain better intra- and intermolecular properties, with significant improvements obtained in the reproduction of experimental heats of sublimation for indole and free energies of aqueous solvation for methylindole.     

Force-field parameters for the simulation of tetrahedral intermediates of serine hydrolases

CHARMM force-field parameters are reported for the tetrahedral intermediate of serine hydrolases. The fitting follows the standard protocol proposed for CHARMM22. The reference data include ab initio (RHF/6-31G*) interaction energies of complexes between water and the model compound 1,1-dimethoxyethoxide, torsional profiles of related model compounds from correlated ab initio (MP2/6-311+G*//B3LYP/6-31+G*) calculations, as well as molecular geometries and vibrational frequencies from density functional theory (B3LYP/6-31+G*). The optimized parameters reproduce the target data well. Their utility is demonstrated by a QM/MM study of the tetrahedral intermediate in Bacillus subtilis lipase A, and by classical molecular modeling of enantioselectivity in Pseudomonas aeruginosa lipase and its mutants.