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.     

Force field development for organic molecules: Modifying dihedral and 1–n pair interaction parameters

We comprehensively illustrate a general process of fitting all‐atom molecular mechanics force field (FF) parameters based on quantum mechanical calculations and experimental thermodynamic data. For common organic molecules with free dihedral rotations, this FF format is comprised of the usual bond stretching, angle bending, proper and improper dihedral rotation, and 1–4 scaling pair interactions. An extra format of 1–n scaling pair interaction is introduced when a specific intramolecular rotation is strongly hindered. We detail how the preferred order of fitting all intramolecular FF parameters can be determined by systematically generating characteristic configurations. The intermolecular Van der Waals parameters are initially taken from the literature data but adjusted to obtain a better agreement between the molecular dynamics (MD) simulation results and the experimental observations if necessary. By randomly choosing the molecular configurations from MD simulation and comparing their energies computed from FF parameters and quantum mechanics, the FF parameters can be verified self‐consistently. Using an example of a platform chemical 3‐hydroxypropionic acid, we detail the comparison between the new fitting parameters and the existing FF parameters. In particular, the introduced systematic approach has been applied to obtain the dihedral angle potential and 1–n scaling pair interaction parameters for 48 organic molecules with different functionality. We suggest that this procedure might be used to obtain better dihedral and 1–n interaction potentials when they are not available in the current widely used FF. © 2014 Wiley Periodicals, Inc.     

Force field development for cofactors in the photosystem II

We present a set of force field (FF) parameters compatible with the AMBER03 FF to describe five cofactors in photosystem II (PSII) of oxygenic photosynthetic organisms: plastoquinone‐9 (three redox forms), chlorophyll‐a, pheophytin‐a, heme‐b, and β‐carotene. The development of a reliable FF for these cofactors is an essential step for performing molecular dynamics simulations of PSII. Such simulations are important for the calculation of absorption spectrum and the further investigation of the electron and energy transfer processes. We have derived parameters for partial charges, bonds, angles, and dihedral‐angles from solid theoretical models using systematic quantum mechanics (QM) calculations. We have shown that the developed FF parameters are in good agreement with both ab initio QM and experimental structural data in small molecule crystals as well as protein complexes. © 2012 Wiley Periodicals, Inc.     

Homology modeling,force field design,and free energy simulation studies to optimize the activities of histone deacetylase inhibitors

As an effort to develop therapeutics for cancer treatments, a number of effective histone deacetylase inhibitors with structural diversity have been discovered. To gain insight into optimizing the activity of an identified lead compound, a computational protocol sequentially involving homology modeling, docking experiments, molecular dynamics simulation, and free energy perturbation calculations was applied for rationalizing the relative activities of known histone deacetylase inhibitors. With the newly developed force field parameters for the coordination environment of the catalytic zinc ion in hand, the computational strategy proved to be successful in predicting the rank orders for 12 derivatives of three hydroxamate-based inhibitor scaffolds with indole amide, pyrrole, and sulfonamide moieties. The results showed that the free energy of an inhibitor in aqueous solution should be an important factor in determining the binding free energy. Hence, in order to enhance the inhibitory activity by adding or substituting a chemical group, the increased stabilization in solution due to the structural changes must be overcome by a stronger enzyme-inhibitor interaction. It was also found that to optimize inhibitor potency, the hydrophobic head of an inhibitor should be elongated or enlarged so that it can interact with Pro29 and His28 that are components of the flexible loop at the top of the active site.     

Force field evaluation for biomolecular simulation: free enthalpies of solvation of polar and apolar compounds in various solvents.

Recently, the GROMOS biomolecular force field parameter set 53A6--which has been parametrized to reproduce experimentally determined free enthalpies of hydration and solvation in cyclohexane of amino acid side-chain analogs--was presented. To investigate the transferability of the new parameter set, we calculated free enthalpies of solvation of a range of polar and apolar compounds in different solvents (methanol, dimethyl sulfoxide (DMSO), acetonitrile, and acetone) from molecular dynamics simulations using the GROMOS 53A6 force field. For methanol and DMSO, parameters were used that are available in the 53A6 parameter set. For acetonitrile, a recently developed model was taken and for acetone, two models available in literature were used. We found that trends in and values for the solvation free enthalpies are in satisfactory agreement with experiment, except for the solvation in acetone for which deviations from experiment can be explained in terms of the properties of the models used.     

Force field parameters for rotation around chi torsion axis in nucleic acids

To raise the accuracy of the force field for nucleic acids, several parameters were elaborated, focusing on the rotation around chi torsion axis. The reliability of molecular dynamics (MD) simulation was significantly increased by improving the torsion parameters at C8--N9--C1'--X (X = H1', C2', O4') in A, G and those at C6--N1--C1'--X in C, T, and U. In this work, we constructed small models representing the chemical structure of A, G, C, T, and U, and estimated energy profile for chi-axis rotation by executing numerous quantum mechanical (QM) calculations. The parameters were derived by discrete Fourier transformation of the calculated QM data. A comparison in energy profile between molecular mechanical (MM) calculation and QM one shows that our presently derived parameters well reproduce the energy surface of QM calculation for all the above torsion terms. Furthermore, our parameters show a good performance in MD simulations of some nucleic acids. Hence, the present refinement of parameters will enable us to perform more accurate simulations for various types of nucleic acids.     

New all-atom force field for molecular dynamics simulation of an AlPO(4)-34 molecular sieve

A force field of the triclinic framework of AlPO(4)-34, important in methanol-hydrocarbon conversion reactions, was developed using an empirical potential function. Molecular dynamics simulation of an AlPO(4)-34 triclinic framework segment of 1216 atoms, containing the template molecules isopropylamine and water, was performed with explicit consideration of atomic charges. The average RMS difference between instantaneous positions of the framework atoms during 1 ns simulation and their positions in the structure determined from single crystal X-ray diffraction was calculated, and the average structure of the flexible framework was determined. The computed Debye-Waller factors and simulated FTIR spectra are in good agreement with the experimental data. The new force field permits detailed molecular dynamics simulations of flexible, charged aluminophosphate molecular sieves which should lead to a better understanding of the catalytic processes and the crucial role played by templating molecules.     

Additive CHARMM force field for naturally occurring modified ribonucleotides

More than 100 naturally occurring modified nucleotides have been found in RNA molecules, in particular in tRNAs. We have determined molecular mechanics force field parameters compatible with the CHARMM36 all‐atom additive force field for all these modifications using the CHARMM force field parametrization strategy. Emphasis was placed on fine tuning of the partial atomic charges and torsion angle parameters. Quantum mechanics calculations on model compounds provided the initial set of target data, and extensive molecular dynamics simulations of nucleotides and oligonucleotides in aqueous solutions were used for further refinement against experimental data. The presented parameters will allow for computational studies of a wide range of RNAs containing modified nucleotides, including the ribosome and transfer RNAs. © 2016 The Authors. Journal of Computational Chemistry Published by Wiley Periodicals, Inc.     

Enrichments of post‐translational modifications in proteomic studies

More than 300 different protein post‐translational modifications are currently known, but only a few have been extensively investigated because modified proteoforms are commonly present in sub‐stoichiometry amount. For this reason, improvement of specific enrichment techniques is particularly useful for the proteomic characterization of post‐translationally modified proteins. Enrichment proteomic strategies could help the researcher in the challenging issue to decipher the complex molecular cross‐talk existing between the different factors influencing the cellular pathways. In this review the state of art of the platforms applied for the enrichment of specific and most common post‐translational modifications, such as glycosylation and glycation, phosphorylation, sulfation, redox modifications (i.e. sulfydration and nitrosylation), methylation, acetylation, and ubiquitinylation, are described. Enrichments strategies applied to characterize less studied post‐translational modifications are also briefly discussed.     

Evaluation of solvation free energies for small molecules with the AMOEBA polarizable force field

The effects of electronic polarization in biomolecular interactions will differ depending on the local dielectric constant of the environment, such as in solvent, DNA, proteins, and membranes. Here the performance of the AMOEBA polarizable force field is evaluated under nonaqueous conditions by calculating the solvation free energies of small molecules in four common organic solvents. Results are compared with experimental data and equivalent simulations performed with the GAFF pairwise‐additive force field. Although AMOEBA results give mean errors close to “chemical accuracy,” GAFF performs surprisingly well, with statistically significantly more accurate results than AMOEBA in some solvents. However, for both models, free energies calculated in chloroform show worst agreement to experiment and individual solutes are consistently poor performers, suggesting non‐potential‐specific errors also contribute to inaccuracy. Scope for the improvement of both potentials remains limited by the lack of high quality experimental data across multiple solvents, particularly those of high dielectric constant. © 2016 The Authors. Journal of Computational Chemistry Published by Wiley Periodicals, Inc.     

An improved nucleic acid parameter set for the GROMOS force field

Over the past decades, the GROMOS force field for biomolecular simulation has primarily been developed for performing molecular dynamics (MD) simulations of polypeptides and, to a lesser extent, sugars. When applied to DNA, the 43A1 and 45A3 parameter sets of the years 1996 and 2001 produced rather flexible double-helical structures, in which the Watson-Crick hydrogen-bonding content was more limited than expected. To improve on the currently available parameter sets, the nucleotide backbone torsional-angle parameters and the charge distribution of the nucleotide bases are reconsidered based on quantum-chemical data. The new 45A4 parameter set resulting from this refinement appears to perform well in terms of reproducing solution NMR data and canonical hydrogen bonding. The deviation between simulated and experimental observables is now of the same order of magnitude as the uncertainty in the experimental values themselves.     

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.     

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.     

United atom force field for phospholipid membranes: Constant pressure molecular dynamics simulation of dipalmitoylphosphatidicholine/water system

We refined the united atom field for the simulations of phospholipid membranes. To validate this potential we performed 1000-ps constant pressure simulation of a dipalmitoylphosphatidicholine (DPPC) bilayer at T=50° C. The average area per head group (61.6±0.6) Ų obtained in our simulation agrees well with the measured one of (62.9±1.3) Ų. The calculated S_CD order parameters for the Sn-2 hydrocarbon tail also display a good agreement with the experiment. The conformations of head groups in our simulations of the liquid crystal phase are different than the ones observed in the crystal structure. ©1999 John Wiley & Sons, Inc. J Comput Chem 20, 531–545, 1999     

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.     

Modification of the CHARMM force field for DMPC lipid bilayer

The CHARMM force field for DMPC lipids was modified in order to improve agreement with experiment for a number of important properties of hydrated lipid bilayer. The modification consists in introduction of a scaling factor 0.83 for 1-4 electrostatic interactions (between atoms separated by three covalent bonds), which provides correct transgauche ratio in the alkane tails, and recalculation of the headgroup charges on the basis of HF/6-311(d,p) ab-initio computations. Both rigid TIP3P and flexible SPC water models were used with the new lipid model, showing similar results. The new model in a 75 ns simulation has shown a correct value of the area per lipid at zero surface tension, as well as good agreement with the experiment for the electron density, structure factor, and order parameters, including those in the headgroup part of lipids.