Extension of the GLYCAM06 Biomolecular Force Field to Lipids, Lipid Bilayers and Glycolipids

GLYCAM06 is a generalisable biomolecular force field that is extendible to diverse molecular classes in the spirit of a small-molecule force field. Here we report parameters for lipids, lipid bilayers and glycolipids for use with GLYCAM06. Only three lipid-specific atom types have been introduced, in keeping with the general philosophy of transferable parameter development. Bond stretching, angle bending, and torsional force constants were derived by fitting to quantum mechanical data for a collection of minimal molecular fragments and related small molecules. Partial atomic charges were computed by fitting to ensemble-averaged quantum-computed molecular electrostatic potentials.In addition to reproducing quantum mechanical internal rotational energies and experimental valence geometries for an array of small molecules, condensed-phase simulations employing the new parameters are shown to reproduce the bulk physical properties of a DMPC lipid bilayer. The new parameters allow for molecular dynamics simulations of complex systems containing lipids, lipid bilayers, glycolipids, and carbohydrates, using an internally consistent force field. By combining the AMBER parameters for proteins with the GLYCAM06 parameters, it is also possible to simulate protein-lipid complexes and proteins in biologically relevant membrane-like environments.     

GAFF-IC: realistic viscosities for isocyanate molecules with a GAFF-based force field

Aliphatic diisocyanates and their derivatives are key liquid components in the industrial processing of polyurethane materials. In particular, for the synthesis of crosslinked polyurethane materials, the higher functionality molecules obtained by reacting three -or more- diisocyanates are of interest. However, despite their widespread application, the relation between molecular structure and macroscopic physical properties, in particular viscosity, is poorly understood in these systems. In this work, we introduce a new force field parameter set, GAFF-IC, based on the widely-used and versatile GAFF force field, meant for accurate predictions of physical properties of isocyanate-based molecular liquids. The new parameters allow to predict the vaporization enthalpies and densities of several isocyanate-based molecules, which are found in excellent agreement with the available experimental data. The effectiveness and transferability of the improved parameters is verified by calculating the viscosities of several isocyanates, isocyanate dimers (uretdiones) and isocyanate trimers (isocyanurates), resulting in accurate viscosity predictions in excellent agreement with experimental values.     

Molecular dynamics simulation of hen egg white lysozyme: a test of the GROMOS96 force field against nuclear magnetic resonance data

Biomolecular force fields for use in molecular dynamics (MD) simulations of proteins, DNA, or membranes are generally parametrized against ab initio quantum-chemical and experimental data for small molecules. The application of a force field in a simulation of a biomolecular system, such as a protein in solution, may then serve as a test of the quality and transferability of the force field. Here, we compare various properties obtained from two MD simulations of the protein hen egg white lysozyme (HEWL) in aqueous solution using the latest version, GROMOS96, of the GROMOS force field and an earlier version, GROMOS87+, with data derived from nuclear magnetic resonance (NMR) experiments: NOE atom-atom distance bounds, (3)J(HNalpha)-coupling constants, and backbone and side-chain order parameters. The convergence of these quantities over a 2-ns period is considered, and converged values are compared to experimental ones. The GROMOS96 simulation shows better agreement with the NMR data and also with the X-ray crystal structure of HEWL than the GROMOS87+ simulation, which was based on an earlier version of the GROMOS force field.     

Determination method of the balance of the secondary-structure-forming tendencies of force fields

We propose a new method of optimisation of backbone torsion-energy parameters in the force field for molecular simulations of protein systems. This method is based on the idea of balancing the secondary-structure-forming tendencies, namely, those of α-helix and β-sheet structures. We perform a minimisation of the backbone dihedral angle-based root-mean-square deviation of the helix and β structure regions in many protein structures. As an example, we optimised the backbone torsion-energy parameters of AMBER parm96 force field using 100 protein molecules from the Protein Data Bank. We then performed folding simulations of α-helical and β-hairpin peptides, using the optimised force field. The results imply that the new force-field parameters give structures more consistent with the experimental implications than the original AMBER parm96 force field.     

Parameterization of aromatic azido groups: application as photoaffinity probes in molecular dynamics studies

The accuracy of molecular dynamics (MD) simulations is limited by the availability of parameters for the molecular system of interest. In most force fields, parameters of common chemical groups are already present. With the development of novel small organic molecules as probes to study biological systems, more chemical groups require parameterization. An azide group is often used in studies of biological systems but computational studies are still impeded by the lack of parameters. In this paper, we present a set of molecular mechanics (MM) parameters for aromatic and aliphatic azido groups, and their application in MD simulations of a photoaffinity probe currently used in our laboratory for mapping binding modes available in the active site of histone deacetylases. The parameters were developed for the generalized Amber force field (GAFF) using density functional theory (DFT) calculations at B3LYP 6-311G(d) level. The parameters were validated by geometry optimization and MD simulations.     

Optimisation of OPLS–UA force-field parameters for protein systems using protein data bank

We have previously proposed a method for refining force-field parameters of protein systems, which consists of minimising the summation of the square of the force acting on each atom in the proteins with the structures from the protein data bank (PDB). The results showed that the modified force-field parameters for all-atom model gave structures more consistent with the experimental implications than the original force fields. In this work, we applied this method and a new method to the OPLS–UA force field. In the new method, we perform a minimisation of the average of the root-mean-square deviation of various protein structures from the native structure. We selected some torsion-energy parameters for this optimisation, and 100 molecules from the PDB were used. The results imply that the new force-field parameters gave structures of two peptides more consistent with the experimental implications for the secondary structure-forming tendencies than the original OPLS–UA force field.     

Protein Structure Prediction with a Combined Solvation Free Energy-Molecular Mechanics Force Field

Abstract

Models of protein structure are frequently used to determine the physical characteristics of a protein when the crystal structure is not available. We developed a procedure to optimize such models, by use of a combined solvation free energy and molecular mechanics force field. Appropriately chosen atomic solvation parameters were defined using the criterion that the resulting protein model should deviate least from the crystal structure upon a forty picosecond molecular dynamics simulation carried out using the combined force field. Several tests were performed to refine the set of atomic solvation parameters which best complement the molecular mechanics forces. Four sets of parameters from the literature were tested and an empirically optimized set is proposed. The parameters are defined on a well characterized small molecule (alanyl dipeptide) and on the highly refined crystal structure of rat trypsin, and then tested on a second highly refined crystal structure of α-lytic protease. The new set of atomic solvation parameters provides a significant improvement over molecular mechanics alone in energy minimization of protein structures. This combined force field also has advantages over the use of explicit solvent as it is possible to take solvent effects into account during energetic conformational searching when modeling a homologous protein structure from a known crystal structure.     

The consistency of large concerted motions in proteins in molecular dynamics simulations.

A detailed investigation is presented into the effect of limited sampling time and small changes in the force field on molecular dynamics simulations of a protein. Thirteen independent simulations of the B1 IgG-binding domain of streptococcal protein G were performed, with small changes in the simulation parameters in each simulation. Parameters studied included temperature, bond constraints, cut-off radius for electrostatic interactions, and initial placement of hydrogen atoms. The essential dynamics technique was used to reveal dynamic differences between the simulations. Similar essential dynamics properties were found for all simulations, indicating that the large concerted motions found in the simulations are not particularly sensitive to small changes in the force field. A thorough investigation into the stability of the essential dynamics properties as derived from a molecular dynamics simulation of a few hundred picoseconds is provided. Although the definition of the essential modes of motion has not fully converged in these short simulations, the subspace in which these modes are confined is found to be reproducible.     

COMPASS II: extended coverage for polymer and drug-like molecule databases

The COMPASS II force field has been developed by extending the coverage of the COMPASS force field (J Phys Chem B 102(38):7338–7364, 1998) to polymer and drug-like molecules found in popular databases. Using a fragmentation method to systematically construct small molecules that exhibit key functional groups found in these databases, parameters applicable to database compounds were efficiently obtained. Based on the same parameterization paradigm as used in the development of the COMPASS force field, new parameters were derived by a combination of fits to quantum mechanical data for valence parameters and experimental liquid and crystal data for nonbond parameters. To preserve the quality of the original COMPASS parameters, a quality assurance suite was used and updated to ensure that additional atom-types and parameters do not interfere with the existing ones. Validation against molecular properties, liquid and crystal densities, and enthalpies, demonstrates that the quality of COMPASS is preserved and the same quality of prediction is achieved for the additional coverage.     

Parametric sensitivity analysis of avian pancreatic polypeptide (APP)

Computer simulations utilizing a classical force field have been widely used to study biomolecular properties. It is important to identify the key force field parameters or structural groups controlling the molecular properties. In the present paper the sensitivity analysis method is applied to study how various partial charges and solvation parameters affect the equilibrium structure and free energy of avian pancreatic polypeptide (APP). The general shape of APP is characterized by its three principal moments of inertia. A molecular dynamics simulation of APP was carried out with the OPLS/Amber force field and a continuum model of solvation energy. The analysis pinpoints the parameters which have the largest (or smallest) impact on the protein equilibrium structure (i.e., the moments of inertia) or free energy. A display of the protein with its atoms colored according to their sensitivities illustrates the patterns of the interactions responsible for the protein stability. The results suggest that the electrostatic interactions play a more dominant role in protein stability than the part of the solvation effect modeled by the atomic solvation parameters. © 1995 Wiley-Liss, Inc.     

Towards the simulation of biomolecules: optimisation of peptide-capped glycine using FFLUX

Abstract

The optimisation of a peptide-capped glycine using the novel force field FFLUX is presented. FFLUX is a force field based on the machine-learning method kriging and the topological energy partitioning method called Interacting Quantum Atoms. FFLUX has a completely different architecture to that of traditional force fields, avoiding (harmonic) potentials for bonded, valence and torsion angles. In this study, FFLUX performs an optimisation on a glycine molecule and successfully recovers the target density-functional-theory energy with an error of 0.89 ± 0.03 kJ mol^?1. It also recovers the structure of the global minimum with a root-mean-squared deviation of 0.05 Å (excluding hydrogen atoms). We also show that the geometry of the intra-molecular hydrogen bond in glycine is recovered accurately.     

Evolutionally guided enzyme design

A combination of "rational" and "irrational" strategies for the creation of enzymes with novel properties is proving to be a powerful concept in the field of enzyme engineering. Guided by principles of physical organic chemistry, rational design strategies are used to identify suitable target enzymes and to choose appropriate molecular biological methods for engineering purposes. In contrast, irrational (or random) strategies are centered around the biological paradigm of stochastic molecular evolution. As illustrated in this review, such a hybrid approach is particularly useful for the design of new modular enzymes. (c) 1996 John Wiley & Sons, Inc.     

Harmonic force field for nitro compounds

Molecular simulations leading to sensors for the detection of explosive compounds require force field parameters that can reproduce the mechanical and vibrational properties of energetic materials. We developed precise harmonic force fields for alanine polypeptides and glycine oligopeptides using the FUERZA procedure that uses the Hessian tensor (obtained from ab initio calculations) to calculate precise parameters. In this work, we used the same procedure to calculate generalized force field parameters of several nitro compounds. We found a linear relationship between force constant and bond distance. The average angle in the nitro compounds was 116°, excluding the 90° angle of the carbon atoms in the octanitrocubane. The calculated parameters permitted the accurate molecular modeling of nitro compounds containing many functional groups. Results were acceptable when compared with others obtained using methods that are specific for one type of molecule, and much better than others obtained using methods that are too general (these ignore the chemical effects of surrounding atoms on the bonding and therefore the bond strength, which affects the mechanical and vibrational properties of the whole molecule).     

Globally optimised parameters for a model of mitotic control in frog egg extracts

DNA synthesis and nuclear division in the developing frog egg are controlled by fluctuations in the activity of M-phase promoting factor (MPF). The biochemical mechanism of MPF regulation is most easily studied in cytoplasmic extracts of frog eggs, for which careful experimental studies of the kinetics of phosphorylation and dephosphorylation of MPF and its regulators have been made. In 1998 Marlovits et al. used these data sets to estimate the kinetic rate constants in a mathematical model of the control system originally proposed by Novak & Tyson. In a recent publication, we showed that a gradient-based optimisation algorithm finds a locally optimal parameter set quite close to the 'Marlovits' estimates. In this paper, we combine global and local optimisation strategies to show that the 'refined Marlovits' parameter set, with one minor but significant modification to the Novak & Tyson equations, is the unique, best-fitting solution to the parameter estimation problem.     

Self-Rotation of Cells in an Irrotational AC E-Field in an Opto-Electrokinetics Chip

The use of optical dielectrophoresis (ODEP) to manipulate microparticles and biological cells has become increasingly popular due to its tremendous flexibility in providing reconfigurable electrode patterns and flow channels. ODEP enables the parallel and free manipulation of small particles on a photoconductive surface on which light is projected, thus eliminating the need for complex electrode design and fabrication processes. In this paper, we demonstrate that mouse cells comprising melan-a cells, RAW 267.4 macrophage cells, peripheral white blood cells and lymphocytes, can be manipulated in an opto-electrokinetics (OEK) device with appropriate DEP parameters. Our OEK device generates a non-rotating electric field and exerts a localized DEP force on optical electrodes. Hitherto, we are the first group to report that among all the cells investigated, melan-a cells, lymphocytes and white blood cells were found to undergo self-rotation in the device in the presence of a DEP force. The rotational speed of the cells depended on the voltage and frequency applied and the cells'' distance from the optical center. We discuss a possible mechanism for explaining this new observation of induced self-rotation based on the physical properties of cells. We believe that this rotation phenomenon can be used to identify cell type and to elucidate the dielectric and physical properties of cells.     

Importance of the CMAP correction to the CHARMM22 protein force field: dynamics of hen lysozyme

The recently developed CMAP correction to the CHARMM22 force field (C22) is evaluated from 25 ns molecular dynamics simulations on hen lysozyme. Substantial deviations from experimental backbone root mean-square fluctuations and N-H NMR order parameters obtained in the C22 trajectories (especially in the loops) are eliminated by the CMAP correction. Thus, the C22/CMAP force field yields improved dynamical and structural properties of proteins in molecular dynamics simulations.     

Effect of partial atomic charges on the calculated free energy of solvation of poly(vinyl alcohol) in selected solvents

It is well-known that properties of poly(vinyl alcohol) (PVA) in the pure and solution states depend largely on the hydrogen bonding networks formed. In the context of molecular simulation, such networks are handled through the Coulombic interactions. Therefore, a good set of partial atom charges (PACs) for simulations involving PVA is highly desirable. In this work, we calculated the PACs for PVA using a few commonly used population analysis schemes with a hope to identify an accurate set of PACs for PVA monomers. To evaluate the quality of the calculated parameters, we have benchmarked their predictions for free energy of solvation (FES) in selected solvents by molecular dynamics simulations against the ab initio calculated values. Selected solvents were water, ethanol and benzene as they covered a range of size and polarity. Also, PVA with different tacticities were used to capture their effect on the calculated FESs. Based on our results, neither PACs nor FESs are affected by the chain tacticity. While PACs predicted by the Merz-Singh-Kollman scheme were close to original values in the OPLS-AA force field in way that no significant difference in properties of pure PVA was observed, free energy of solvation calculated using such PACs showed greater agreement with ab initio calculated values than those calculated by OPLS-AA (and all other schemes used in this work) in all three solvents considered.     

Evaluation of models for the evolution of protein sequences and functions under structural constraint

In the field of evolutionary structural genomics, methods are needed to evaluate why genomes evolved to contain the fold distributions that are observed. In order to study the effects of population dynamics in the evolved genomes we need fast and accurate evolutionary models which can analyze the effects of selection, drift and fixation of a protein sequence in a population that are grounded by physical parameters governing the folding and binding properties of the sequence. In this study, various knowledge-based, force field, and statistical methods for protein folding have been evaluated with four different folds: SH2 domains, SH3 domains, Globin-like, and Flavodoxin-like, to evaluate the speed and accuracy of the energy functions. Similarly, knowledge-based and force field methods have been used to predict ligand binding specificity in SH2 domain. To demonstrate the applicability of these methods, the dynamics of evolution of new binding capabilities by an SH2 domain is demonstrated.     

Validation of molecular force field parameters for peptides including isomerized amino acids

Recently, stereoinversions and isomerizations of amino acid residues in the proteins of living beings have been observed. Because isomerized amino acids cause structural changes and denaturation of proteins, isomerizations of amino acid residues are suspected to cause age‐related diseases. In this study, AMBER molecular force field parameters were tested by using computationally generated nonapeptides and tripeptides including stereoinverted and/or isomerized amino acid residues. Energy calculations by using density functional theory were also performed for comparison. Although the force field parameters were developed by parameter fitting for l ‐α‐amino acids, the accuracy of the computational results for d ‐amino acids and β‐amino acids was comparable to those for l ‐α‐amino acids. The conformational energies for tripeptides calculated by using density functional theory were reproduced more accurately than those for nonapeptides calculated by using the molecular mechanical force field. The evaluations were performed for the ff99SB, ff03, ff12SB, and the latest ff14SB force field parameters.