An electronic structure-based polarization method, called the X-POL potential, has been described for the purpose of constructing an empirical force field for modeling polypeptides. In the X-POL potential, the internal, bonded interactions are fully represented by an electronic structure theory augmented with some empirical torsional terms. Non-bonded interactions are modeled by an iterative, combined quantum mechanical and molecular mechanical method, in which the molecular mechanical partial charges are derived from the molecular wave functions of the individual fragments. In this paper, the feasibility of such an electronic structure force field is illustrated by small model compounds. A method has been developed for separating a polypeptide chain into peptide units and its parameterization procedure in the X-POL potential is documented and tested on glycine dipeptide. We envision that the next generation of force fields for biomolecular polymer simulations will be developed based on electronic structure theory, which can adequately define and treat many-body polarization and charge delocalization effects.
The efficient and accurate characterization of solvent effects is a key element in the theoretical and computational study of biological problems. Implicit solvent models, particularly generalized Born (GB) continuum electrostatics, have emerged as an attractive tool to study the structure and dynamics of biomolecules in various environments. Despite recent advances in this methodology, there remain limitations in the parameterization of many of these models. In the present work, we demonstrate that it is possible to achieve a balanced implicit solvent force field by further optimizing the input atomic radii in combination with adjusting the protein backbone torsional energetics. This parameter optimization is guided by the potentials of mean force (PMFs) between amino acid polar groups, calculated from explicit solvent free energy simulations, and by conformational equilibria of short peptides, obtained from extensive folding and unfolding replica exchange molecular dynamics (REX-MD) simulations. Through the application of this protocol, the delicate balance between the competing solvation forces and intramolecular forces appears to be better captured, and correct conformational equilibria for a range of both helical and β-hairpin peptides are obtained. The same optimized force field also successfully folds both beta-hairpin trpzip2 and mini-protein Trp-Cage...
We report the development of ICMFF, new force field parameterized using a combination of experimental data for crystals of small molecules and quantum mechanics calculations. The main features of ICMFF include: (a) parameterization for the dielectric constant relevant to the condensed state (ε=2) instead of vacuum; (b) an improved description of hydrogen-bond interactions using duplicate sets of van der Waals parameters for heavy atom-hydrogen interactions; and (c) improved backbone covalent geometry and energetics achieved using novel backbone torsional potentials and inclusion of the bond angles at the Cα atoms into the internal variable set. The performance of ICMFF was evaluated through loop modeling simulations for 4-13 residue loops. ICMFF was combined with a solvent-accessible surface area solvation model optimized using a large set of loop decoys. Conformational sampling was carried out using the Biased Probability Monte Carlo method. Average/median backbone root-mean-square deviations of the lowest energy conformations from the native structures were 0.25/0.21 Å for 4 residues loops, 0.84/0.46 Å for 8 residue loops, and 1.16/0.73 Å for 12 residue loops. To our knowledge, these results are significantly better than or comparable to those reported to date for any loop modeling method that does not take crystal packing into account. Moreover...
We study the lipid and phase transferability of our recently developed systematically coarse-grained solvent-free membrane model. The force field was explicitly parameterized to describe a fluid 1-palmitoyl-2-oleoyl-phosphatidylcholine (POPC) bilayer at 310 K with correct structure and area per lipid, while gaining at least three orders of magnitude in computational efficiency (see Wang and Deserno 2010 J. Phys. Chem. B 114 11207–20). Here, we show that exchanging CG tails, without any subsequent re-parameterization, creates reliable models of 1,2-dioleoylphosphatidylcholine (DOPC) and 1,2-dipalmitoylphosphatidylcholine (DPPC) lipids in terms of structure and area per lipid. Furthermore, all CG lipids undergo a liquid–gel transition upon cooling, with characteristics like those observed in experiments and all-atom simulations during phase transformation. These studies suggest a promising transferability of our force field parameters to different lipid species and thermodynamic state points, properties that are a prerequisite for even more complex systems, such as mixtures.
A classical nonpolarizable force field is presented for the simulation of aqueous alkali halide solutions (MX), where M = Li+, Na+, K+, Rb+, Cs+ and X = F−, Cl−, Br−, I−, and their interactions with biomolecules. The models are specifically designed to reproduce the experimental Kirkwood-Buff integrals, and thereby the solution salt activities, as a function of salt concentration. Additionally, we demonstrate that these models reasonably reproduce other experimental properties including ion diffusion constants, dielectric decrements, and the excess heats of mixing. The parameters are developed by considering the properties of aqueous NaX and MCl solutions using a previously established model for NaCl. Transferability of the parameters to other salts is then established by the successful simulation of additional aqueous salt solutions, KI and CsBr, not originally included in the parameterization procedure.
Molecular dynamics simulations hold the promise of providing an atomic-level description of protein folding that cannot easily be obtained from experiments. Here, we examine the extent to which the molecular mechanics force field used in such simulations might influence the observed folding pathways. To that end, we performed equilibrium simulations of a fast-folding variant of the villin headpiece using four different force fields. In each simulation, we observed a large number of transitions between the unfolded and folded states, and in all four cases, both the rate of folding and the structure of the native state were in good agreement with experiments. We found, however, that the folding mechanism and the properties of the unfolded state depend substantially on the choice of force field. We thus conclude that although it is important to match a single, experimentally determined structure and folding rate, this does not ensure that a given simulation will provide a unique and correct description of the full free-energy surface and the mechanism of folding.
We introduce a toolset of program libraries collectively titled MATCH (Multipurpose Atom-Typer for CHARMM) for the automated assignment of atom types and force field parameters for molecular mechanics simulation of organic molecules. The toolset includes utilities for the conversion from multiple chemical structure file formats into a molecular graph. A general chemical pattern-matching engine using this graph has been implemented whereby assignment of molecular mechanics atom types, charges and force field parameters is achieved by comparison against a customizable list of chemical fragments. While initially designed to complement the CHARMM simulation package and force fields by generating the necessary input topology and atom-type data files, MATCH can be expanded to any force field and program, and has core functionality that makes it extendable to other applications such as fragment-based property prediction. In the present work, we demonstrate the accurate construction of atomic parameters of molecules within each force field included in CHARMM36 through exhaustive cross validation studies illustrating that bond increment rules derived from one force field can be transferred to another. In addition, using leave-one-out substitution it is shown that it is also possible to substitute missing intra and intermolecular parameters with ones included in a force field to complete the parameterization of novel molecules. Finally...
A protocol to generate parameters for the AMOEBA polarizable force field for small organic molecules has been established, and polarizable atomic typing utility, Poltype, which fully automates this process, has been implemented. For validation, we have compared with quantum mechanical calculations of molecular dipole moments, optimized geometry, electrostatic potential, and conformational energy for a variety of neutral and charged organic molecules, as well as dimer interaction energies of a set of amino acid side chain model compounds. Furthermore, parameters obtained in gas phase are substantiated in liquid-phase simulations. The hydration free energy (HFE) of neutral and charged molecules have been calculated and compared with experimental values. The RMS error for the HFE of neutral molecules is less than 1 kcal/mol. Meanwhile, the relative error in the predicted HFE of salts (cations and anions) is less than 3% with a correlation coefficient of 0.95. Overall, the performance of Poltype is satisfactory and provides a convenient utility for applications such as drug discovery. Further improvement can be achieved by the systematic study of various organic compounds, particularly ionic molecules, and refinement and expansion of the parameter database.
A polarizable force field of saturated phosphatidylcholine-containing lipids based on the classical Drude oscillator model is optimized and used in molecular dynamics simulations of bilayer and monolayer membranes. The hierarchical parameterization strategy involves the optimization of parameters for small molecules representative of lipid functional groups, followed by their application in larger model compounds and full lipids. The polar head group is based on molecular ions tetramethyl ammonium and dimethyl phosphate, the esterified glycerol backbone is based on methyl acetate, and the aliphatic lipid hydrocarbon tails are based on linear alkanes. Parameters, optimized to best represent a collection of gas and liquid properties for these compounds, are assembled into a complete model of dipalmitoylphosphatidylcholine (DPPC) lipids that is tested against the experimental properties of bilayer and monolayer membranes. The polarizable model yields average structural properties that are in broad accord with experimental data. The area per lipid of the model is 60 Å2, slightly smaller than the experimental value of 63 Å2. The order parameters from nuclear magnetic resonance deuterium quadrupolar splitting measures, the electron density profile...
Coarse-grained (CG) simulation methods are now widely used to model the structure and dynamics of large biomolecular systems. One important issue for using such methods – especially with regard to using them to model, for example, intracellular environments – is to demonstrate that they can reproduce experimental data on the thermodynamics of protein-protein interactions in aqueous solutions. To examine this issue, we describe here simulations performed using the popular coarse-grained MARTINI force field, aimed at computing the thermodynamics of lysozyme and chymotrypsinogen self-interactions in aqueous solution. Using molecular dynamics simulations to compute potentials of mean force between a pair of protein molecules, we show that the original parameterization of the MARTINI force field is likely to significantly overestimate the strength of protein-protein interactions to the extent that the computed osmotic second virial coefficients are orders of magnitude more negative than experimental estimates. We then show that a simple down-scaling of the van der Waals parameters that describe the interactions between protein pseudo-atoms can bring the simulated thermodynamics into much closer agreement with experiment. Overall, the work shows that it is feasible to test explicit-solvent CG force fields directly against thermodynamic data for proteins in aqueous solutions...
Classical molecular dynamics (MD) simulations based on atomistic models are increasingly used to study a wide range of biological systems. A prerequisite for meaningful results from such simulations is an accurate molecular mechanical force field. Most biomolecular simulations are currently based on the widely used AMBER and CHARMM force fields, which were parameterized and optimized to cover a small set of basic compounds corresponding to the natural amino acids and nucleic acid bases. Atomic models of additional compounds are commonly generated by analogy to the parameter set of a given force field. While this procedure yields models that are internally consistent, the accuracy of the resulting models can be limited. In this work, we propose a method, General Automated Atomic Model Parameterization (GAAMP), for generating automatically the parameters of atomic models of small molecules using the results from ab initio quantum mechanical (QM) calculations as target data. Force fields that were previously developed for a wide range of model compounds serve as initial guess, although any of the final parameter can be optimized. The electrostatic parameters (partial charges, polarizabilities and shielding) are optimized on the basis of QM electrostatic potential (ESP) and...
The inability to rapidly generate accurate and robust parameters for novel chemical matter continues to severely limit the application of molecular dynamics (MD) simulations to many biological systems of interest, especially in fields such as drug discovery. Although the release of generalized versions of common classical force fields, e.g., GAFF and CGenFF, have posited guidelines for parameterization of small molecules, many technical challenges remain that have hampered their wide-scale extension. The Force Field Toolkit (ffTK), described herein, minimizes common barriers to ligand parameterization through algorithm and method development, automation of tedious and error-prone tasks, and graphical user interface design. Distributed as a VMD plugin, ffTK facilitates the traversal of a clear and organized workflow resulting in a complete set of CHARMM-compatible parameters. A variety of tools are provided to generate quantum mechanical target data, set up multidimensional optimization routines, and analyze parameter performance. Parameters developed for a small test set of molecules using ffTK were comparable to existing CGenFF parameters in their ability to reproduce experimentally measured values for pure-solvent properties (<15% error from experiment) and free energy of solvation (±0.5 kcal/mol from experiment).
In a continuation of our efforts to develop a united atom non-polarizable protein force field based upon the solution theory of Kirkwood and Buff i.e., the Kirkwood-Buff Force Field (KBFF) approach, we present KBFF models for the side chains of phenylalanine, tyrosine, tryptophan, and histidine, including both tautomers of neutral histidine and doubly-protonated histidine. The force fields were specifically designed to reproduce the thermodynamic properties of mixtures over the full composition range in an attempt to provide an improved description of intermolecular interactions. The models were developed by careful parameterization of the solution phase partial charges to reproduce the experimental Kirkwood-Buff integrals for mixtures of solutes representative of the amino acid sidechains in solution. The KBFF parameters and simulated thermodynamic and structural properties are presented for the following eleven binary mixtures: benzene + methanol, benzene + toluene, toluene + methanol, toluene + phenol, toluene + p-cresol, pyrrole + methanol, indole + methanol, pyridine + methanol, pyridine + water, histidine + water, and histidine hydrochloride + water. It is argued that the present approach and models provide a reasonable description of intermolecular interactions which ensures that the required balance between solute-solute...
The explicit polarization (X-Pol) theory is a fragment-based quantum chemical method that explicitly models the internal electronic polarization and intermolecular interactions of a chemical system. X-Pol theory provides a framework to construct a quantum mechanical force field, which we have extended to liquid hydrogen fluoride (HF) in this work. The parameterization, called XPHF, is built upon the same formalism introduced for the XP3P model of liquid water, which is based on the polarized molecular orbital (PMO) semiempirical quantum chemistry method and the dipole-preserving polarization consistent point charge model. We introduce a fluorine parameter set for PMO, and find good agreement for various gas-phase results of small HF clusters compared to experiments and ab initio calculations at the M06-2X/MG3S level of theory. In addition, the XPHF model shows reasonable agreement with experiments for a variety of structural and thermodynamic properties in the liquid state, including radial distribution functions, interaction energies, diffusion coefficients, and densities at various state points.
An extensible polarizable force field for transition metal ion was developed based on AMOEBA and the angular overlap model (AOM) with consistent treatment of electrostatics for all atoms. Parameters were obtained by fitting molecular mechanics (MM) energies to various ab initio gas-phase calculations. The results of parameterization were presented for copper (II) ion ligated to water and model fragments of amino acid residues involved in the copper binding sites of type 1 copper proteins. Molecular dynamics (MD) simulations were performed on aqueous copper (II) ion at various temperatures, as well as plastocyanin (1AG6) and azurin (1DYZ). Results demonstrated that the AMOEBA-AOM significantly improves the accuracy of classical MM in a number of test cases when compared to ab initio calculations. The Jahn-Teller distortion for hexa-aqua copper (II) complex was handled automatically without specifically designating axial and in-plane ligands. Analyses of MD trajectories resulted in a 6-coordination first solvation shell for aqueous copper (II) ion and a 1.8ns average residence time of water molecules. The ensemble average geometries of 1AG6 and 1DYZ copper binding sites were in general agreement with X-ray and previous computational studies.
The continued development and utility of molecular dynamics simulations requires improvements in both the physical models used (force fields) and in our ability to sample the Boltzmann distribution of these models. Recent developments in both areas have made available multi-microsecond simulations of two proteins, ubiquitin and Protein G, using a number of different force fields. Although these force fields mostly share a common mathematical form, they differ in their parameters and in the philosophy by which these were derived, and previous analyses showed varying levels of agreement with experimental NMR data. To complement the comparison to experiments, we have performed a structural analysis of and comparison between these simulations, thereby providing insight into the relationship between force-field parameterization, the resulting ensemble of conformations and the agreement with experiments. In particular, our results show that, at a coarse level, many of the motional properties are preserved across several, though not all, force fields. At a finer level of detail, however, there are distinct differences in both the structure and dynamics of the two proteins, which can, together with comparison with experimental data, help to select force fields for simulations of proteins. A noteworthy observation is that force fields that have been reparameterized and improved to provide a more accurate energetic description of the balance between helical and coil structures are difficult to distinguish from their “unbalanced” counterparts in these simulations. This observation implies that simulations of stable...
Tese de mestrado, Bioquímica, Universidade de Lisboa, Faculdade de Ciências, 2010; In 2009, Machuqueiro and Baptista used Desulfovibrio vulgaris Hildenborough type I cytochrome c3 in the validation of their new implementation of the stochastic titration method, the constant-(pH,E) MD method. DvH-TpI-c3 is a small globular and monomeric tetraheme protein present in the periplasm of the sulfate reducing bacteria DvH. It is constituted by 107 residues plus four hemes covalently bound to cysteines in the polypeptide chain together with bis-histidinyl axial ligation. Therefore, it constitutes a tight densely packed structure where the heme reduction potentials are very close, making it a very demanding test case in terms of prediction. When tested, this method was shown to yield better results when a high dielectric constant, ", was assigned to the protein region. This dependence on " was never found in previous constant-pH MD simulations and poor heme charge parameterization may have been responsible for this effect. Hence, the main goal of this work was to refine the QM parameterization of the redox centers, i.e. obtain new and more accurate charge sets, incorporate them in the new 53A6 GROMOS force field, and finally run constant-(pH...
In this data article we provide topologies and force field parameters files for molecular dynamics simulations of lipids in the OPLS-aa force field using the GROMACS package. This is the first systematic parameterization of lipid molecules in this force field. Topologies are provided for four phosphatidylcholines: saturated DPPC, mono-cis unsaturated POPC and DOPC, and mono-trans unsaturated PEPC. Parameterization of the phosphatidylcholines was achieved in two steps: first, we supplemented the OPLS force field parameters for DPPC with new parameters for torsion angles and van der Waals parameters for the carbon and hydrogen atoms in the acyl chains, as well as new partial atomic charges and parameters for torsion angles in the phosphatidylcholine and glycerol moieties . Next, we derived parameters for the cis and trans double bonds and the neighboring them single bonds . Additionally, we provide GROMACS input files with parameters describing simulation conditions (md.mdp), which are strongly recommended to be used with these lipids models. The data are associated with the research article “Cis and trans unsaturated phosphatidylcholine bilayers: a molecular dynamics simulation study”  and provided as supporting materials.
The method and the advantages of an evolutionary computing based approach
using a steady state genetic algorithm (GA) for the parameterization of
interatomic potentials for metal oxides within the shell model framework are
developed and described. We show that the GA based methodology for the
parameterization of interatomic force field functions is capable of (a)
simultaneous optimization of the multiple phases or properties of a material in
a single run, (b) facilitates the incremental re-optimization of the whole
system as more data is available for either additional phases or material
properties not included in previous runs, and (c) successful global
optimization in the presence of multiple local minima in the parameter space.
As an example, we apply the method towards simultaneous optimization of four
distinct crystalline phases of Barium Titanate (BaTiO3 or BTO) using an ab
initio density functional theory (DFT) based reference dataset. We find that
the optimized force field function is capable of the prediction of the two
phases not used in the optimization procedure, and that many derived physical
properties such as the equilibrium lattice constants, unit cell volume, elastic
properties, coefficient of thermal expansion, and average electronic
polarization are in good agreement with the experimental results available from
the literature.; Comment: 31 pages...
Parameterization of a reactive force field for NaH is done using ab initio derived data. The parameterized force field(ReaxFFNaH) is used to study the dynamics governing hydrogen desorption in NaH. During the abstraction process of surface molecular hydrogen charge transfer is found to be well described by the parameterized force field. To gain more insight into the mechanism governing structural transformation of NaH during thermal decomposition a heating run in a molecular dynamics simulation is done. The result shows that a clear signature of hydrogen desorption is the fall in potential energy surface during heating.