OPLS-AA Force Field Research Articles

Insights on the Origin of Catalysis on Glycine N-Methyltransferase from Computational Modeling.

The origin of enzyme catalysis remains a question of debate despite much intense study. We report a QM/MM theoretical study of the SN2 methyl transfer reaction catalyzed by a glycine N-methyltransferase (GNMT) and three mutants to test whether recent experimental observations of rate-constant reductions and variations in inverse secondary α-3H kinetic isotope effects (KIEs) should be attributed to changes in the methyl donor-acceptor distance (DAD): Is catalysis due to a compression effect? Semiempirical (AM1) and DFT (M06-2X) methods were used to describe the QM subset of atoms, while OPLS-AA and TIP3P classical force fields were used for the protein and water molecules, respectively. The computed activation free energies and KIEs are in good agreement with experimental data, but the mutations do not meaningfully affect the DAD: Compression cannot explain the experimental variations on KIEs. On the contrary, electrostatic properties in the active site correlate with the catalytic activity of wild type and mutants. The plasticity of the enzyme moderates the effects of the mutations, explaining the rather small degree of variation in KIEs and reactivities.

Molecular dynamics simulation for the test of calibrated OPLS-AA force field for binary liquid mixture of tri-iso-amyl phosphate and n-dodecane.

Tri-isoamyl phosphate (TiAP) has been proposed to be an alternative for tri-butyl phosphate (TBP) in the Plutonium Uranium Extraction (PUREX) process. Recently, we have successfully calibrated and tested all-atom optimized potentials for liquid simulations using Mulliken partial charges for pure TiAP, TBP, and dodecane by performing molecular dynamics (MD) simulation. It is of immense importance to extend this potential for the various molecular properties of TiAP and TiAP/n-dodecane binary mixtures using MD simulation. Earlier, efforts were devoted to find out a suitable force field which can explain both structural and dynamical properties by empirical parameterization. Therefore, the present MD study reports the structural, dynamical, and thermodynamical properties with different mole fractions of TiAP-dodecane mixtures at the entire range of mole fraction of 0-1 employing our calibrated Mulliken embedded optimized potentials for liquid simulation (OPLS) force field. The calculated electric dipole moment of TiAP was seen to be almost unaffected by the TiAP concentration in the dodecane diluent. The calculated liquid densities of the TiAP-dodecane mixture are in good agreement with the experimental data. The mixture densities at different temperatures are also studied which was found to be reduced with temperature as expected. The plot of diffusivities for TiAP and dodecane against mole fraction in the binary mixture intersects at a composition in the range of 25%-30% of TiAP in dodecane, which is very much closer to the TBP/n-dodecane composition used in the PUREX process. The excess volume of mixing was found to be positive for the entire range of mole fraction and the excess enthalpy of mixing was shown to be endothermic for the TBP/n-dodecane mixture as well as TiAP/n-dodecane mixture as reported experimentally. The spatial pair correlation functions are evaluated between TiAP-TiAP and TiAP-dodecane molecules. Further, shear viscosity has been computed by performing the non-equilibrium molecular dynamics employing the periodic perturbation method. The calculated shear viscosity of the binary mixture is found to be in excellent agreement with the experimental values. The use of the newly calibrated OPLS force field embedding Mulliken charges is shown to be equally reliable in predicting the structural and dynamical properties for the mixture without incorporating any arbitrary scaling in the force field or Lennard-Jones parameters. Further, the present MD simulation results demonstrate that the Stokes-Einstein relation breaks down at the molecular level. The present methodology might be adopted to evaluate the liquid state properties of an aqueous-organic biphasic system, which is of great significance in the interfacial science and technology.

Molecular dynamics study of surfactant-modified water–carbon dioxide systems

Alternating water/ flooding is known to be very efficient for enhanced oil recovery, but is often economically infeasible for small sources. A similar effect can be achieved indirectly via injection of water– mixture with low molecular-weight emulsifiers with affinity for polar segments of residual hydrocarbons. To investigate the potential of this approach, we have performed molecular simulations of N-acetyl morpholine (NAM) and N-formyl morpholine (NFM) surfactants in liquid – systems at K and Atm. The surfactants were modelled by means of the OPLSAA force field, with quantum mechanical calculations used to obtain the partial charges. Our simulations clearly showed the affinity of both NAM and NFM for the – interface, providing extensive evidence of their interfacial activity. We also present an intuitive technique aiming to find and analyse intrinsic surfaces that define liquid-liquid interfaces by utilizing instantaneous and time averaged atomic configurations. This analysis allowed us to quantify the impact of NAM and NFM on the intrinsic surface structure of in liquid – systems. Our results indicate that the instantaneous structure of intrinsic surface will be significantly roughened by the presence of NAM and NFM.

Development of an AMBER-compatible transferable force field for poly(ethylene glycol) ethers (glymes).

An all-atom force field consistent with the general AMBER force field (GAFF) format for poly(ethylene glycol) dimethyl ether (diglyme or G2) was developed by fitting to experimental liquid densities and dielectric constants. Not surprisingly, the new force field gives excellent agreement with experimental liquid phase densities and dielectric constants over a wide temperature range. Other dynamic and thermodynamic properties of liquid G2 such as its self-diffusion coefficient, shear viscosity, and vaporization enthalpy were also calculated and compared to experimental data. For all of the properties studied, the performance of the proposed new force field is better than that of the standard GAFF force field. The force field parameters were transferred to model two other poly(ethylene glycol) ethers: monoglyme (G1) and tetraglyme (G4). The predictive ability of the modified force field for G1 and G4 was significantly better than that of the original GAFF force field. The proposed force field provides an alternative option for the simulation of mixtures containing glymes using GAFF-compatible force fields, particularly for electrochemical applications. The accuracy of a previously published force field based on the OPLS-AA format and the accuracies of two modified versions of that force field were also examined for G1, G2, and G4. It was found that the original OPLS-AA force field is superior to the modified versions of it, and that it has a similar accuracy to the proposed new GAFF-compatible force field. Graphical abstract Transferability of an AMBER-compatible force field parameterized for G2 to other glymes.

Developing and Validating a Set of All-Atom Potential Models for Sodium Dodecyl Sulfate.

We present a set of novel all-atom potential models for sodium dodecyl sulfate (SDS), developed within the framework of the widely used OPLS-AA and General AMBER force fields. The choice of the parameters for the models is made by rigorously following the methodology of the used force fields to ensure full compatibility with the models for other compounds. For the GAFF model, extensive quantum-chemical computations are performed to obtain reliable Boltzmann-averaged atomic point charges, and the latter are compared with the single-conformation charges. For representation of the hydrocarbon tail, we use recently published improved parameters that correctly reproduce the properties of lipids and long alkanes. The models are validated on the basis of correct reproduction of the main properties of micelles (size, degree of counterion binding) as well as diffusion coefficient of the SDS monomer. As an extended test, a simulation of a micelle with a high aggregation number (382) and unnatural initial shape is performed, and a restructuring to the correct shape is observed. This proves the suitability of the developed models for simulations of concentrated SDS solutions containing large micelles and also emphasizes importance of hydrocarbon tail parameters for the micelle properties. Finally, the developed DS- models are tested in combination with several common Na+ and water models. Their effect on the properties of SDS micelles is discussed, and suitable combinations are determined.

Accuracy Test of the OPLS-AA Force Field for Calculating Free Energies of Mixing and Comparison with PAC-MAC.

We have calculated the excess free energy of mixing of 1053 binary mixtures with the OPLS-AA force field using two different methods: thermodynamic integration (TI) of molecular dynamics simulations and the Pair Configuration to Molecular Activity Coefficient (PAC-MAC) method. PAC-MAC is a force field based quasi-chemical method for predicting miscibility properties of various binary mixtures. The TI calculations yield a root mean squared error (RMSE) compared to experimental data of 0.132 kBT (0.37 kJ/mol). PAC-MAC shows a RMSE of 0.151 kBT with a calculation speed being potentially 1.0 × 104 times greater than TI. OPLS-AA force field parameters are optimized using PAC-MAC based on vapor–liquid equilibrium data, instead of enthalpies of vaporization or densities. The RMSE of PAC-MAC is reduced to 0.099 kBT by optimizing 50 force field parameters. The resulting OPLS-PM force field has a comparable accuracy as the OPLS-AA force field in the calculation of mixing free energies using TI.

Molecular Dynamics Simulations of Lithium Ion Transport through Solid Electrolyte Interface Layer

Lithium ion transport through solid electrode interface (SEI) layer is elusive to molecular simulation studies due to lack of composition information and force field parameters available for organic SEI layer. Last decade, dilithium diethylene carbonate (Li2EDC) was suggested as the primary component of SEI layer using experiments and quantum mechanical simulations. We applied classical, non-polarizable OPLS-AA force field parameters to model SEI layer of Li2EDC molecules. Long time-scale molecular simulations at various temperatures (333, 500, 700K) were performed to calculate structural and transport properties of lithium ion in EDC. Vibrational power spectral analysis suggested two prominent modes of lithium vibrations at frequencies 400 and 650 cm-1 in EDC and pure ethylene carbonate solvents. These vibrational modes were further confirmed in Gaussian electronic structure calculations results. Self part of time dependent correlation function calculated using van Hove function confirm that EDC is crystalline compared to pure ethylene carbonate. Sandia National Laboratories (SNL) is a multi-mission laboratory managed and operated by Sandia Corporation, a wholly owned subsidiary of Lockheed Martin Corporation, for the U.S. Department of Energy's (DOE) National Nuclear Security Administration under Contract DE-AC04-94AL85000.

Improved treatment of nucleosides and nucleotides in the OPLS-AA force field

DFT calculations have been used to develop improved descriptions of the torsional energetics for nucleosides and nucleotides in the OPLS-AA force field. Scans of nucleotide dihedral angles (γ, χ, and β) and methyl phosphates provided the bases for the new torsional parameters. In addition, the angle-bending parameters of phosphodiesters and ribose were updated, and adjustments were made to existing carbohydrate torsions to better capture the sugar puckering landscape of ribose. MD simulations of nucleosides with the new parameters demonstrate a significant improvement in the ribose sugar puckering and χ angle distributions. Additionally, energy-minimization of protein-nucleotide crystal structures with the new parameters produced accurate poses.

Conformational Sampling of a Biomolecular Rugged Energy Landscape.

The protein structure refinement using conformational sampling is important in hitherto protein studies. In this paper, we examined the protein structure refinement by means of potential energy minimization using immune computing as a method of sampling conformations. The method was tested on the x-ray structure and 30 decoys of the mutant of [Leu]Enkephalin, a paradigmatic example of the biomolecular multiple-minima problem. In order to score the refined conformations, we used a standard potential energy function with the OPLSAA force field. The effectiveness of the search was assessed using a variety of methods. The robustness of sampling was checked by the energy yield function which measures quantitatively the number of the peptide decoys residing in an energetic funnel. Furthermore, the potential energy-dependent Pareto fronts were calculated to elucidate dissimilarities between peptide conformations and the native state as observed by x-ray crystallography. Our results showed that the probed potential energy landscape of [Leu]Enkephalin is self-similar on different metric scales and that the local potential energy minima of the peptide decoys are metastable, thus they can be refined to conformations whose potential energy is decreased by approximately 250 kJ/mol.

Counting the Relative Number of Hydrogen Bonds in Several Alcohol Co-Solvated Systems via GROMACS

In order to better understand the solubility properties of polyalkane, polyether and polysilicone materials, which are critical to the foaming behavior of shampoo and shaving creams, GROMACS molecular dynamics NVT simulations were performed using the OPLS-AA force field to determine the time-average number of hydrogen bonds in solutions of water co-solvated with methanol, ethanol, isopropanol, dimethyl ketone and acetyl methyl carbinol.

All-atom molecular dynamics simulations of lung surfactant protein B: Structural features of SP-B promote lipid reorganization

Lung surfactant protein B (SP-B), a 79 residue, hydrophobic protein from the saposin superfamily, plays an essential role in breathing. Because of the extreme hydrophobicity of SP-B, the experimental structure of this protein has not yet been determined. Here, we run all-atom molecular dynamics simulations using the OPLS-AA force field in GROMACS to study SP-B's structure and mechanisms for promoting lipid reorganization. Firstly, we find that the final structures indicate the need for some fine-tuning of the homology-based secondary structure predictions. Secondly, we find energetically feasible structures 1) with SP-B's helices in the plane of the bilayer, 2) with SP-B's helices inclined with respect to the bilayer, and 3) with SP-B in a closed structure interacting peripherally with the bilayer. Interestingly, SP-B structures that were bent at the hinge region between the pairs of helices promoted and/or stabilized defects in the lipid bilayer. Finally, particular salt bridge patterns and structural plasticity in the central loop and adjacent region of SP-B appeared to be involved in SP-B's lipid reorganization abilities.

Prediction of cyclohexane-water distribution coefficients for the SAMPL5 data set using molecular dynamics simulations with the OPLS-AA force field.

All-atom molecular dynamics simulations were used to predict water-cyclohexane distribution coefficients [Formula: see text] of a range of small molecules as part of the SAMPL5 blind prediction challenge. Molecules were parameterized with the transferable all-atom OPLS-AA force field, which required the derivation of new parameters for sulfamides and heterocycles and validation of cyclohexane parameters as a solvent. The distribution coefficient was calculated from the solvation free energies of the compound in water and cyclohexane. Absolute solvation free energies were computed by an established protocol using windowed alchemical free energy perturbation with thermodynamic integration. This protocol resulted in an overall root mean square error in [Formula: see text] of almost 4 log units and an overall signed error of -3 compared to experimental data. There was no substantial overall difference in accuracy between simulating in NVT and NPT ensembles. The signed error suggests a systematic error but the experimental [Formula: see text] data on their own are insufficient to uncover the source of this error. Preliminary work suggests that the major source of error lies in the hydration free energy calculations.

Partitioning of butanol between a hydrophobic ionic liquid and aqueous phase: Insights from Liquid Liquid Equilibria measurements and Molecular Dynamics simulations

This work investigates the effectiveness of 1-methyl-3-octylimidazolium bis (trifluoromethylsulfonyl) imide, [OMIM] [Tf2N] as a solvent to recover 1-butanol from aqueous stream. The solvent [OMIM] [Tf2N] (1.320 g/cm3) possessed a higher density and formed two clear and distinct phases after extraction. Both Liquid-Liquid Equilibrium (LLE) experimental studies and Molecular Dynamic (MD) simulation were carried out for [OMIM] [Tf2N]-1-butanol-water system to explain the effectiveness of the solvent. A type II phase behavior with a large immiscible region was observed for the system at T = 298.15 K and p = 1 atm. High values of selectivity ranging from 555 to 3583 have been observed for 1-butanol extraction. The distribution coefficients were also found to be greater than unity. The experiments indicated an easier separation of solute from aqueous phase to extract phase. The NMR spectra confirmed the absence of solvent in the water rich phase. NRTL and UNIQUAC models gave root mean square deviation (RMSD) in the range of 0.1%–0.5% for the ternary system. The MD simulations were then performed in an NVT ensemble for a time period of 40 ns using OPLS-AA force field. The first solvation shell for 1-butanol was obtained within 0–4.35 Å and 0–5.75 Å with [OMIM] and [Tf2N] ions respectively. This highlights the fact that butanol molecules are highly solvated by the presence of both ions.

Radical Formation Initiates Solvent-Dependent Unfolding and β-sheet Formation in a Model Helical Peptide

We examined the effects of Cα-centered radical formation on the stability of a model helical peptide, N-Ac-KK(AL)10KK-NH2. Three, 100 ns molecular dynamics simulations using the OPLS-AA force field were carried out on each α-helical peptide in six distinct binary TIP4P water/2,2,2-trifluoroethanol (TFE) mixtures. The α-helicity was at a maximum in 20% TFE, which was inversely proportional to the number of H-bonds between water molecules and the peptide backbone. The radial distribution of TFE around the peptide backbone was highest in 20% TFE, which enhanced helix stability. The Cα-centered radical initiated the formation of a turn within 5 ns, which was a smaller kink at high TFE concentrations, and a loop at lower TFE concentrations. The highest helicity of the peptide radical was measured in 100% TFE. The formation of hydrogen bonds between the peptide backbone and water destabilized the helix, whereas the clustering of TFE molecules around the radical center stabilized the helix. Following radical termination, the once helical structure converted to a β-sheet rich state in 100% water only, and this transition did not occur in the nonradical control peptide. This study gives evidence on how the formation of peptide radicals can initiate α-helical to β-sheet transitions under oxidative stress conditions.

Liquid-liquid phase separation of N-isopropylpropionamide aqueous solutions above the lower critical solution temperature.

We investigate driving forces of the liquid–liquid phase separation of N-isopropylpropionamide (NiPPA) aqueous solutions above the lower critical solution temperature using molecular dynamics simulations. Spontaneous phase separations of the model aqueous solution with a modified OPLS-AA force field are observed above the experimentally determined cloud point. The destabilization toward the phase separation is confirmed by temperature dependence of the long-wavelength limit of the concentration-concentration structure factor, the dominant component of which is found to be an increasing effective attraction between NiPPA molecules. At varying temperatures, the potentials of mean force (PMFs) between a pair of NiPPA molecules at infinite dilution are obtained and decomposed into the nonpolar and Coulombic contributions. The nonpolar contribution, arising essentially from molecular volume, promotes association of NiPPA molecules with increasing temperature while the Coulombic one antagonizes the association. Thus, our analysis leads to a conclusion that the driving force of thermally induced aggregation of NiPPA molecules is the temperature dependence of the nonpolar contribution in PMF between NiPPA molecules, not the temperature dependence of the number or strength of hydrogen bonds between NiPPA and water molecules.

Data including GROMACS input files for atomistic molecular dynamics simulations of mixed, asymmetric bilayers including molecular topologies, equilibrated structures, and force field for lipids compatible with OPLS-AA parameters

In this Data in Brief article we provide a data package of GROMACS input files for atomistic molecular dynamics simulations of multicomponent, asymmetric lipid bilayers using the OPLS-AA force field. These data include 14 model bilayers composed of 8 different lipid molecules. The lipids present in these models are: cholesterol (CHOL), 1-palmitoyl-2-oleoyl-sn-glycero-3-phosphatidylcholine (POPC), 1-palmitoyl-2-oleoyl-sn-glycero-3-phosphatidylethanolamine (POPE), 1-stearoyl-2-oleoyl-sn-glycero-3-phosphatidyl-ethanolamine (SOPE), 1-palmitoyl-2-oleoyl-sn-glycero-3-phosphatidylserine (POPS), 1-stearoyl-2-oleoyl-sn-glycero-3-phosphatidylserine (SOPS), N-palmitoyl-D-erythro-sphingosyl-phosphatidylcholine (SM16), and N-lignoceroyl-D-erythro-sphingosyl-phosphatidylcholine (SM24). The bilayers׳ compositions are based on lipidomic studies of PC-3 prostate cancer cells and exosomes discussed in Llorente et al. (2013) [1], showing an increase in the section of long-tail lipid species (SOPS, SOPE, and SM24) in the exosomes. Former knowledge about lipid asymmetry in cell membranes was accounted for in the models, meaning that the model of the inner leaflet is composed of a mixture of PC, PS, PE, and cholesterol, while the extracellular leaflet is composed of SM, PC and cholesterol discussed in Van Meer et al. (2008) [2]. The provided data include lipids׳ topologies, equilibrated structures of asymmetric bilayers, all force field parameters, and input files with parameters describing simulation conditions (md.mdp). The data is associated with the research article “Interdigitation of Long-Chain Sphingomyelin Induces Coupling of Membrane Leaflets in a Cholesterol Dependent Manner” (Róg et al., 2016) [3].

Understanding the Thermodynamics of Hydrogen Bonding in Alcohol-Containing Mixtures: Cross-Association.

The thermodynamics of hydrogen bonding in 1-alcohol + water binary mixtures is studied using molecular dynamic (MD) simulation and the polar and perturbed chain form of the statistical associating fluid theory (polar PC-SAFT). The fraction of free monomers in pure saturated liquid water is computed using both TIP4P/2005 and iAMOEBA simulation water models. Results are compared to spectroscopic data available in the literature as well as to polar PC-SAFT. Polar PC-SAFT models hydrogen bonds using single bondable association sites representing electron donors and electron acceptors. The distribution of hydrogen bonds in pure alcohols is computed using the OPLS-AA force field. Results are compared to Monte Carlo (MC) simulations available in the literature as well as to polar PC-SAFT. The analysis shows that hydrogen bonding in pure alcohols is best predicted using a two-site model within the SAFT framework. On the other hand, molecular simulations show that increasing the concentration of water in the mixture increases the average number of hydrogen bonds formed by an alcohol molecule. As a result, a transition in association scheme occurs at high water concentrations where hydrogen bonding is better captured within the SAFT framework using a three-site alcohol model. The knowledge gained in understanding hydrogen bonding is applied to model vapor-liquid equilibrium (VLE) and liquid-liquid equilibrium (LLE) of mixtures using polar PC-SAFT. Predictions are in good agreement with experimental data, establishing the predictive power of the equation of state.

Accurate Force Field Parameters and pH Resolved Surface Models for Hydroxyapatite to Understand Structure, Mechanics, Hydration, and Biological Interfaces

Mineralization of bone and teeth involves interactions between biomolecules and hydroxyapatite. Associated complex interfaces and processes remain difficult to analyze at the 1 to 100 nm scale using current laboratory techniques, and prior apatite models for atomistic simulations have been limited in the representation of chemical bonding, surface chemistry, and interfacial interactions. In this contribution, an accurate force field along with pH-resolved surface models for hydroxyapatite is introduced to represent chemical bonding, structural, surface, interfacial, and mechanical properties in quantitative agreement with experiment. The accuracy is orders of magnitude higher in comparison to earlier models and facilitates quantitative monitoring of inorganic-biological assembly. The force field is integrated into the AMBER, CHARMM, CFF, CVFF, DREIDING, GROMACS, INTERFACE, OPLS-AA, and PCFF force fields to enable realistic simulations of apatite-biological systems of any composition and ionic strength. Sp...

Protein Sequence Optimization with a Polarizable Force Field: Insights from PDZ Domains

Computational protein design (CPD) success is currently limited by a number of approximations, which often results in lists of candidate sequences with only a handful of genuine hits. Using a recent extension of the dead-end elimination (DEE) algorithm to many-body potentials, we are able to complement pairwise CPD energy functions with the polarizable AMOEBA force field in a self-consistent reaction field generalized Kirkwood continuum solvent. Results from energetic decompositions and preliminary sequence optimizations suggest solvent effects greatly dampen all but a handful of short-range three-residue interactions. Decompositions with a wild-type dielectric boundary only slightly reduce this damping, suggesting minimal impact of long-range 3-residue energies in implicit solvent models. In addition to these decompositions, we show preliminary sequence optimizations of PDZ domain-ligand complexes using both AMOEBA and OPLS-AA force fields. Differences are observed for both side-chain rotamer preferences and for optimal amino acid sequence. These results pose a series of questions not just about fixed-charge, pairwise decomposable sequence design models, but also our novel polarizable, many-body optimization algorithms and how to use both approaches synergistically.

Conformational and Dynamic Properties of Poly(ethylene oxide) in an Ionic Liquid: Development and Implementation of a First-Principles Force Field.

The conformational properties of polymers in ionic liquids are of fundamental interest but not well understood. Atomistic and coarse-grained molecular models predict qualitatively different results for the scaling of chain size with molecular weight, and experiments on dilute solutions are not available. In this work, we develop a first-principles force field for poly(ethylene oxide) (PEO) in the ionic liquid 1-butyl 3-methylimidazolium tetrafluoroborate ([BMIM][BF4]) using symmetry adapted perturbation theory (SAPT). At temperatures above 400 K, simulations employing both the SAPT and OPLS-AA force fields predict that PEO displays ideal chain behavior, in contrast to previous simulations at lower temperature. We therefore argue that the system shows a transition from extended to more compact configurations as the temperature is increased from room temperature to the experimental lower critical solution temperature. Although polarization is shown to be important, its implicit inclusion in the OPLS-AA force is sufficient to describe the structure and energetics of the mixture. The simulations emphasize the difference between ionic liquids from typical solvents for polymers.