David Poger

An Automated Force Field Topology Builder (ATB) and Repository: Version 1.0

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.

A new force field for simulating phosphatidylcholine bilayers

A new force field for the simulation of dipalmitoylphosphatidylcholine (DPPC) in the liquid‐crystalline, fluid phase at zero surface tension is presented. The structure of the bilayer with the area per lipid (0.629 nm2; experiment 0.629–0.64 nm2), the volume per lipid (1.226 nm3; experiment 1.229–1.232 nm3), and the ordering of the palmitoyl chains (order parameters) are all in very good agreement with experiment. Experimental electron density profiles are well reproduced in particular with regard to the penetration of water into the bilayer. The force field was further validated by simulating the spontaneous assembly of DPPC into a bilayer in water. Notably, the timescale on which membrane sealing was observed using this model appears closer to the timescales for membrane resealing suggested by electroporation experiments than previous simulations using existing models.

On the Validation of Molecular Dynamics Simulations of Saturated and cis-Monounsaturated Phosphatidylcholine Lipid Bilayers: A Comparison with Experiment

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.

Lipid bilayers: the effect of force field on ordering and dynamics

The sensitivity of the structure and dynamics of a fully hydrated pure bilayer of 1,2-dipalmitoyl-sn-glycero-3-phosphocholine (DPPC) in molecular dynamics simulations to changes in force-field and simulation parameters has been assessed. Three related force fields (the Gromos 54A7 force field, a Gromos 53A6-derived parameter set and a variant of the Berger parameters) in combination with either particle-mesh Ewald (PME) or a reaction field (RF) were compared. Structural properties such as the area per lipid, carbon-deuterium order parameters, electron density profile and bilayer thicknesses, are reproduced by all the parameter sets within the uncertainty of the available experimental data. However, there are clear differences in the ordering of the glycerol backbone and choline headgroup, and the orientation of the headgroup dipole. In some cases, the degree of ordering was reminiscent of a liquid-ordered phase. It is also shown that, although the lateral diffusion of the lipids in the plane of the bilayer is often used to validate lipid force fields, because of the uncertainty in the experimental measurements and the fact that the lateral diffusion is dependent on the choice of the simulation conditions, it should not be employed as a measure of quality. Finally, the simulations show that the effect of small changes in force-field parameters on the structure and dynamics of a bilayer is more significant than the treatment of the long-range electrostatic interactions using RF or PME. Overall, the Gromos 54A7 best reproduced the range of experimental data examined.

A ring to rule them all: the effect of cyclopropane fatty acids on the fluidity of lipid bilayers

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.

Effect of Methyl-Branched Fatty Acids on the Structure of Lipid Bilayers

Methyl-branched fatty acids are widespread in prokaryotic membranes. Although anteiso and iso branching (that is on the antepenultimate and penultimate carbons) and the presence of multiple methyl branches in the phytanoyl chain are known to modify the thermotropic behavior and enhance the fluidity of lipid bilayers, little is known about the effect of methyl branching on the structure of lipid bilayers. In this study, molecular dynamics simulations are used to examine systematically the impact of one or more methyl branches at different positions along the sn-1 palmitoyl chain on the structural properties of a 1,2-dipalmitoyl-sn-glycero-3-phosphocholine (DPPC) lipid bilayer. It is found that methyl branching reduces lipid condensation, decreases the bilayer thickness, and lowers chain ordering. Branching also results in the formation of kinks at the branching point, thereby enhancing the fluidity of lipid bilayers. Furthermore, this effect varies in a methyl-position-dependent fashion. In the case of polymethylated chains, the simulations suggest that if the gap between the methyl groups is sufficient (two or three carbons), the effects of the methyl branches are additive and equivalent to the combined effect of the corresponding monomethyl-branched lipids.

Validating lipid force fields against experimental data: Progress, challenges and perspectives

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.

Interplay between glutathione, Atx1 and copper: X-ray absorption spectroscopy determination of Cu(I) environment in an Atx1 dimer.

X-ray absorption techniques have been used to characterise the primary coordination sphere of Cu(I) bound to glutathionate (GS−), to Atx1 and in Cu2I(GS−)2(Atx1)2, a complex recently proposed as the major form of Atx1 in the cytosol. In each complex, Cu(I) was shown to be triply coordinated. When only glutathione is provided, each Cu(I) is triply coordinated by sulphur atoms in the binuclear complex CuI2(GS−)5, involving bridging and terminal thiolates. In the presence of Atx1 and excess of glutathione, under conditions where CuI2(GS−)2(Atx1)2 is formed, each Cu(I) is triply coordinated by sulphur atoms. Given these constraints, there are two different ways for Cu(I) to bridge the Atx1 dimer: either both Cu(I) ions contribute to bridging the dimer, or only one Cu(I) ion is responsible for bridging, the other one being coordinated to two glutathione molecules. These two models are discussed as regards Cu(I) transfer to Ccc2a.

Effect of high pressure on fully hydrated DPPC and POPC bilayers.

Enhanced hydrostatic pressure can induce phase transitions in hydrated lipid bilayers especially those composed of saturated phospholipids. In this work, the phase behavior of fully hydrated DPPC (1,2-dipalmitoyl-sn-glycero-3-phosphocholine) and POPC (2-oleoyl-1-palmitoyl-sn-glycero-3-phosphocholine) bilayers as a function of pressure up to 3000 atm has been examined in atomic detail on time scales of up to 1.0 μs, using the molecular dynamics simulation technique. DPPC bilayers formed a rippled gel-like phase comprising a minor disordered fluid-like region and a major ordered gel-like region at 1000 atm, a partially interdigitated gel-like phase at 2000 atm, and a gel-like phase with most of the lipid acyl chains tilted with respect to the plane of the bilayer at 3000 atm. POPC bilayers formed a rippled gel-like phase at 1800, 2400, and 3000 atm. The phase behavior observed for both DPPC and POPC bilayers is in agreement with experiment. The simulations provide insight into the structural changes of DPPC and POPC bilayers as a function of pressure and demonstrate the ability to model biologically relevant lipid systems under high hydrostatic pressure.

The relative effect of sterols and hopanoids on lipid bilayers: when comparable is not identical

Sterols are the hallmarks of eukaryotic membranes where they are often found in specialized functional microdomains of the plasma membrane called lipid rafts. Despite some notable exceptions, prokaryotes lack sterols. However, growing evidence has suggested the existence of raft-like domains in the plasma membrane of bacteria. A structurally related family of triterpenoids found in some bacteria called hopanoids has long been assumed to be bacterial surrogates for sterols in membranes. Although the effect of sterols, in particular cholesterol, on lipid bilayers has been extensively characterized through experimental and simulation studies, those of hopanoids have hardly been investigated. In this study, molecular dynamics simulations are used to examine the effect of two hopanoids, diploptene (hop-22(29)-ene) and bacteriohopanetetrol ((32R,33S,34S)-bacteriohopane-32,33,34,35-tetrol), on a model bilayer. The results are compared with those obtained for cholesterol and a pure phosphatidylcholine bilayer. It is shown that diploptene and bacteriohopanetetrol behave very differently under the conditions simulated. Whereas bacteriohopanetetrol adopted a cholesterol-like upright orientation in the bilayer, diploptene partitioned between the two leaflets inside the bilayer. Analysis of various structural properties (area per lipid, electron density profile, tilt angle of the lipids, and conformation and order parameters of the phosphatidylcholine tails) in bacteriohopanetetrol- and cholesterol-containing bilayers indicates that the condensing and ordering effect of bacteriohopanetetrol is weaker than that of cholesterol. The simulations suggest that the chemical diversity of hopanoids may lead to a broader range of functional roles in bacterial membranes than sterols in eukaryotic membranes.