The ability of atomic interaction parameters generated using the Automated Topology Builder and Repository version 3.0 (ATB3.0) to predict experimental hydration free enthalpies (ΔG water) and ...solvation free enthalpies in the apolar solvent hexane (ΔG hexane) is presented. For a validation set of 685 molecules the average unsigned error (AUE) between ΔG water values calculated using the ATB3.0 and experiment is 3.8 kJ·mol–1. The slope of the line of best fit is 1.00, the intercept −1.0 kJ·mol–1, and the R 2 0.90. For the more restricted set of 239 molecules used to validate OPLS3 ( J. Chem. Theory Comput. 2016, 12, 281−296, DOI: 10.1021/acs.jctc.5b00864 ) the AUE using the ATB3.0 is just 2.7 kJ·mol–1 and the R 2 0.93. A roadmap for further improvement of the ATB parameters is presented together with a discussion of the challenges of validating force fields against the available experimental data.
Cyclopropane fatty acids are widespread in bacteria. As their concentration increases on exposure to hostile environments, they have been proposed to protect membranes. Here, the effect of ...cyclopropane and unsaturated fatty acids, both in cis and trans configurations, on the packing, order, and fluidity of lipid bilayers is explored using molecular dynamics simulations. It is shown that cyclopropane fatty acids disrupt lipid packing, favor the occurrence of gauche defects in the chains, and increase the lipid lateral diffusion, suggesting that they enhance fluidity. At the same time, they generally induce a greater degree of order than unsaturated fatty acids of the same configuration and limit the rotation about the bonds surrounding the cyclopropane ring. This indicates that cyclopropane fatty acids may fulfill a dual function: stabilizing membranes against adverse conditions while simultaneously promoting their fluidity. Marked differences in the effect of cis- and trans-monocyclopropanated fatty acids were also observed, suggesting that they may play alternative roles in membranes.
Approximately 10% of active galactic nuclei exhibit relativistic jets, which are powered by the accretion of matter onto supermassive black holes. Although the measured width profiles of such jets on ...large scales agree with theories of magnetic collimation, the predicted structure on accretion disk scales at the jet launch point has not been detected. We report radio interferometry observations, at a wavelength of 1.3 millimeters, of the elliptical galaxy M87 that spatially resolve the base of the jet in this source. The derived size of 5.5 ± 0.4 Schwarzschild radii is significantly smaller than the innermost edge of a retrograde accretion disk, suggesting that the M87 jet is powered by an accretion disk in a prograde orbit around a spinning black hole.
Biological membranes display a great diversity in lipid composition and lateral structure that is crucial in a variety of cellular functions. Simulations of membranes have contributed significantly ...to the understanding of the properties, functions and behaviour of membranes and membrane–protein assemblies. This success relies on the ability of the force field used to describe lipid–lipid and lipid–environment interactions accurately, reproducibly and realistically. In this review, we present some recent progress in lipid force-field development and validation strategies. In particular, we highlight how a range of properties obtained from various experimental techniques on lipid bilayers and membranes, can be used to assess the quality of a force field. We discuss the limitations and assumptions that are inherent to both computational and experimental approaches and how these can influence the comparison between simulations and experimental data. This article is part of a Special Issue entitled: Membrane Proteins edited by J.C. Gumbart and Sergei Noskov.
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•A lipid force field needs to be validated against a broad range of properties.•Many properties are highly correlated or interrelated by nature.•Experimental data are limited by the models used to extract and interpret them.•The area per lipid is rather insensitive to methodological aspects of simulations.
Molecular dynamics simulations of fully hydrated pure bilayers of four widely studied phospholipids, 1,2-dilauroyl-sn-glycero-3-phosphocholine (DLPC), 1,2-dimyristoyl-sn-glycero-3-phosphocholine ...(DMPC), 1,2-dioleoyl-sn-glycero-3-phosphocholine (DOPC), and 2-oleoyl-1-palmitoyl-sn-glycero-3-phosphocholine (POPC) using a recent revision of the GROMOS96 force field are reported. It is shown that the force field reproduces the structure and the hydration of bilayers formed by each of the four lipids with high accuracy. Specifically, the solvation and the orientation of the dipole of the phosphocholine headgroup and of the ester carbonyls show that the structure of the primary hydration shell in the simulations closely matches experimental findings. This work highlights the need to reproduce a broad range of properties beyond the area per lipid, which is poorly defined experimentally, and to consider the effect of system size and sampling times well beyond those commonly used.
The Automated force field Topology Builder (ATB, http://compbio.biosci.uq.edu.au/atb) is a Web-accessible server that can provide topologies and parameters for a wide range of molecules appropriate ...for use in molecular simulations, computational drug design, and X-ray refinement. The ATB has three primary functions: (1) to act as a repository for molecules that have been parametrized as part of the GROMOS family of force fields, (2) to act as a repository for pre-equilibrated systems for use as starting configurations in molecular dynamics simulations (solvent mixtures, lipid systems pre-equilibrated to adopt a specific phase, etc.), and (3) to generate force field descriptions of novel molecules compatible with the GROMOS family of force fields in a variety of formats (GROMOS, GROMACS, and CNS). Force field descriptions of novel molecules are derived using a multistep process in which results from quantum mechanical (QM) calculations are combined with a knowledge-based approach to ensure compatibility (as far as possible) with a specific parameter set of the GROMOS force field. The ATB has several unique features: (1) It requires that the user stipulate the protonation and tautomeric states of the molecule. (2) The symmetry of the molecule is analyzed to ensure that equivalent atoms are assigned identical parameters. (3) Charge groups are assigned automatically. (4) Where the assignment of a given parameter is ambiguous, a range of possible alternatives is provided. The ATB also provides several validation tools to assist the user to assess the degree to which the topology generated may be appropriate for a given task. In addition to detailing the steps involved in generating a force field topology compatible with a specific GROMOS parameter set (GROMOS 53A6), the challenges involved in the automatic generation of force field parameters for atomic simulations in general are discussed.
To test and validate the Automated force field Topology Builder and Repository (ATB;
http://compbio.biosci.uq.edu.au/atb/
) the hydration free enthalpies for a set of 214 drug-like molecules, ...including 47 molecules that form part of the SAMPL4 challenge have been estimated using thermodynamic integration and compared to experiment. The calculations were performed using a fully automated protocol that incorporated a dynamic analysis of the convergence and integration error in the selection of intermediate points. The system has been designed and implemented such that hydration free enthalpies can be obtained without manual intervention following the submission of a molecule to the ATB. The overall average unsigned error (AUE) using ATB 2.0 topologies for the complete set of 214 molecules was 6.7 kJ/mol and for molecules within the SAMPL4 7.5 kJ/mol. The root mean square error (RMSE) was 9.5 and 10.0 kJ/mol respectively. However, for molecules containing functional groups that form part of the main GROMOS force field the AUE was 3.4 kJ/mol and the RMSE was 4.0 kJ/mol. This suggests it will be possible to further refine the parameters provided by the ATB based on hydration free enthalpies.
Triclosan and chloroxylenol are broad-spectrum biocides used extensively in healthcare and consumer products. They have been suggested to perturb the structure of bacterial membranes, but studies so ...far have not considered that most bacterial membranes contain large amounts of branched-chain lipids. Here, molecular dynamics simulation is used to examine the effect of the two biocides on membranes consisting of lipids with methyl-branched chains, cyclopropanated chains, and nonbranched chains. It is shown that triclosan and chloroxylenol induced a phase transition in membranes from a liquid-crystalline to a liquid-ordered phase irrespective of the presence and nature of branching groups. At high concentration, chloroxylenol promoted chain interdigitation. Our results suggest that triclosan and chloroxylenol decrease the degree of fluidity of membranes and that this effect is more pronounced in bacterial membranes. As a result, their biocidal activity could be associated with a change in the function of membrane proteins.
The utility of atomistic simulations depends on the accuracy of the force field used to represent the potential energy landscape, the consistency with which interaction parameters can be assigned, ...and the extent to which parameters can be transferred between chemical entities. Here, parameter space mapping, a simple and robust procedure for atom typing (parameter assignment) and parameter optimization, is used to identify a minimal set of parameters capable of simultaneously reproducing the density, heat of vaporization, and solvation free energies for a targeted set of simple hydrocarbons. Using an atom-centered fixed charge model and a 6–12 Lennard–Jones potential, the experimental densities and the heats of vaporization for 22 hydrocarbons (linear, cyclic, and aromatic) could be predicted with high precision: average unsigned error (AUE) of 6.1 kg/m3 and 0.5 kJ/mol, respectively, and R 2 values of 0.991 and 0.999, respectively. For the 17 compounds with experimental solvation free energy values in water, the AUE was 1.3 kJ/mol, and the slope and R 2 for the line of best fit were 0.968 and 0.991, respectively. A key element in ensuring transferability in this work was minimizing confounding variables by ensuring that the calculation of observables was independent of the precise choice of simulation settings (cutoff, bond constraints, etc.) and the explicit consideration of correlations between parameters.
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