ORCID Profile
0000-0001-8794-5688
Current Organisation
Microscopy Australia
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Publisher: Wiley
Date: 28-09-2023
DOI: 10.1111/JMI.13230
Publisher: Elsevier BV
Date: 07-2016
DOI: 10.1016/J.BBAMEM.2016.01.029
Abstract: Biological membranes display a great ersity 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.
Publisher: Springer Science and Business Media LLC
Date: 13-08-2008
DOI: 10.1007/S00775-008-0408-1
Abstract: 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.
Publisher: American Chemical Society (ACS)
Date: 03-12-2013
DOI: 10.1021/JP409748D
Abstract: 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 ersity of hopanoids may lead to a broader range of functional roles in bacterial membranes than sterols in eukaryotic membranes.
Publisher: American Chemical Society (ACS)
Date: 22-09-2020
Publisher: American Chemical Society (ACS)
Date: 19-11-2014
DOI: 10.1021/JP503910R
Abstract: 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.
Publisher: American Chemical Society (ACS)
Date: 04-06-2019
Abstract: 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.
Publisher: Royal Society of Chemistry (RSC)
Date: 2018
DOI: 10.1039/C7CP06776C
Abstract: This work studies the mechanisms by which hydronium ions modulate the structure of phospholipid bilayers.
Publisher: American Chemical Society (ACS)
Date: 03-11-2014
DOI: 10.1021/JZ5020778
Abstract: Sterols and hopanoids have been suggested to reinforce membranes and protect against unfavorable environmental conditions. In particular, hopanoids are found in high concentrations in membranes of thermotolerant and thermophilic bacteria. However, the mechanism whereby sterols and hopanoids stabilize membranes at elevated temperatures is poorly understood. Here, the effect of temperature on the ordering of lipids in bilayers containing cholesterol or the hopanoids bacteriohopanetetrol and diplopterol was explored using molecular dynamics simulations. It is shown that cholesterol induces a high level of ordering over a wide range of temperatures. Bacteriohopanetetrol promotes order within the lipid tails but enhances fluid-like properties of the head groups at high temperatures. In contrast, diplopterol partitions in the midplane of the bilayer. This suggests that in idual hopanoids fulfill distinct functions in membranes, with the ordering properties of bacteriohopanetetrol being particularly well suited to maintain the integrity of membranes at temperatures preferred by thermotolerant and thermophilic bacteria.
Publisher: American Chemical Society (ACS)
Date: 16-04-2015
Abstract: 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.
Publisher: Wiley
Date: 12-09-2005
DOI: 10.1016/J.FEBSLET.2005.08.052
Abstract: Molecular dynamics simulations were performed on both apo and copper forms of the human copper chaperone, Hah1. Wild-type Hah1 and a methionine (M10) to serine mutant were investigated. We have evidenced the central role of residue M10 in stabilizing the hydrophobic core of Hah1 as well as the internal structure of the metal-binding site. When copper(I) is bound, the mobility of Hah1 is reduced whereas mutation of M10 implies a drastic increase of the mobility of apoHah1, stressing the importance of this highly conserved hydrophobic residue for copper sequestration by the apoprotein.
Publisher: Wiley
Date: 15-03-2006
DOI: 10.1002/JCC.20392
Abstract: We have developed new force field and parameters for copper(I) and mercury(II) to be used in molecular dynamics simulations of metalloproteins. Parameters have been derived from fitting of ab initio interaction potentials calculated at the MP2 level of theory, and results compared to experimental data when available. Nonbonded parameters for the metals have been calculated from ab initio interaction potentials with TIP3P water. Due to high charge transfer between Cu(I) or Hg(II) and their ligands, the model is restricted to a linear coordination of the metal bonded to two sulfur atoms. The experimentally observed asymmetric distribution of metal ligand bond lengths (r) is accounted for by the addition of an anharmonic (r3) term in the potential. Finally, the new parameters and potential, introduced into the CHARMM force field, are tested in short molecular dynamics simulations of two metal thiolates fragments in water. (Brooks BR et al. J Comput Chem 1983, 4, 1987.1).
Publisher: Springer Science and Business Media LLC
Date: 15-09-2018
Publisher: Wiley
Date: 18-08-2016
Abstract: An interpretation of alternative crystal structures of the erythropoietin receptor, with and without ligand, led to the proposal of a scissor-like mechanism of activation. This model has been propagated in the literature and is still being used to interpret crystal structures of related type-I cytokine receptors. Here, we assess whether the model remains compatible with current knowledge on the family of type-I cytokine receptors, and consider whether the model, as initially presented, is truly supported by the crystal structures on which it was originally based.
Publisher: Wiley
Date: 18-02-2013
Publisher: Elsevier BV
Date: 02-2017
Publisher: American Chemical Society (ACS)
Date: 31-01-2020
Abstract: This study investigates the effect of hydronium ions (H
Publisher: American Chemical Society (ACS)
Date: 03-09-2010
DOI: 10.1021/CT1003934
Abstract: The prolactin receptor resides on the surface of the cell as a preformed dimer. This suggests that cell signaling is triggered by conformational changes within the extracellular domain of the receptors. Here, by using atomistic molecular dynamics simulations, we show that the removal of the ligand placental lactogen from the dimeric form of the prolactin receptor results in a relative reorientation of the two extracellular domains by 20-30°, which corresponds to a clockwise rotation of the domains with respect to each other. Such a mechanism of activation for the prolactin receptor is similar to that proposed previously in the case of the growth hormone receptor. In addition to the effect of the removal of the ligand, the mechanical coupling between the extracellular and transmembrane domains within a model membrane was also examined.
Publisher: Wiley
Date: 17-12-2020
Abstract: α-Helical membrane-active antimicrobial peptides (AMPs) are known to act via a range of mechanisms, including the formation of barrel-stave and toroidal pores and the micellisation of the membrane (carpet mechanism). Different mechanisms imply that the peptides adopt different 3D structures when bound at the water-membrane interface, a highly hipathic environment. Here, an evolutionary algorithm is used to predict the 3D structure of a range of α-helical membrane-active AMPs at the water-membrane interface by optimising hipathicity. This hipathic structure prediction (ASP) is capable of distinguishing between curved and linear peptides solved experimentally, potentially allowing the activity and mechanism of action of different membrane-active AMPs to be predicted. The ASP algorithm is accessible via a web interface at atb.uq.edu.au/asp/.
Publisher: American Chemical Society (ACS)
Date: 23-11-2010
DOI: 10.1021/CT900487A
Abstract: 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 s ling times well beyond those commonly used.
Publisher: Zenodo
Date: 2021
Publisher: American Chemical Society (ACS)
Date: 17-04-2014
DOI: 10.1021/BI401632Z
Abstract: The cell surface epidermal growth factor receptor (EGFR) plays a critical role in cell development and oncogenesis. The binding of growth factors to the EGFR results in a mechanical signal being transmitted through the plasma membrane. In this study, atomistic molecular dynamics simulations have been used to investigate the conformational changes associated with the binding of the epidermal growth factor (EGF) and transforming growth factor α (TGFα) to the EGFR. In the simulations, the removal of the EGF and TGFα from the extracellular domain of the EGFR homodimer led to a relative rotation of the protomers of 16-35° about the dimerization axis. The three N-terminal domains that make up the extracellular region of the receptor undergo essentially rigid-body motion. The dimerization interface itself was found to be largely unaffected by the removal of the ligand. In most simulations, the rotation within the dimer was associated with an opening of the cytokine-binding sites. On the basis of these simulations, a simple mechanical model that explains the coupling between the binding of ligand and the motions in the extracellular domains is proposed.
Publisher: American Chemical Society (ACS)
Date: 14-10-2015
DOI: 10.1021/ACS.LANGMUIR.5B02635
Abstract: Fatty acids containing a terminal cyclic group such as cyclohexyl and cycloheptyl are commonly found in prokaryotic membranes, especially in those of thermo-acidophilic bacteria. These so-called ω-alicyclic fatty acids have been proposed to stabilize the membranes of bacteria by reducing the fluidity in membranes and increasing lipid packing and lipid chain order. In this article, molecular dynamics simulations are used to examine the effect of 3- to 7-membered cycloalkyl saturated and unsaturated (cyclopent-2-enyl and phenyl) rings in ω-alicyclic fatty acyl chains on the structure (lipid packing, lipid chain order, and fraction of gauche defects in the chains) and dynamics (lateral lipid diffusion) of a model lipid bilayer. It was found that ω-alicyclic chains in which the ring was saturated reduced lipid condensation and lowered chain order which would be associated with enhanced fluidity. However, this effect was limited. The lateral diffusion of the lipids diminished as the ring size increased. In particular, ω-cyclohexyl and ω-cycloheptyl acyl tails led to a decrease in lipid diffusion. In contrast, ω-alicyclic acyl chains that contain an unsaturated ring promoted membrane fluidity both in terms of changes in membrane structure and lipid diffusion. This may indicate that saturated and unsaturated terminal rings in ω-alicyclic fatty acids fulfill alternative functions within membranes. Overall, the simulations suggest that ω-alicyclic fatty acids in which the terminal ring is saturated might protect the membrane of thermo-acidophilic bacteria from high-temperature and low-pH conditions through a "dynamical barrier" that would limit lipid diffusion and transmembrane diffusion of undesired ions and molecules.
Publisher: American Chemical Society (ACS)
Date: 26-05-2017
Abstract: To enhance efficiency in molecular dynamics simulations, forces that vary slowly are often evaluated less often than those that vary rapidly. We show that the multiple-time-step algorithm implemented in recent versions of GROMACS results in significant differences in the collective properties of a system under conditions where the system was previously stable. The implications of changing the simulation algorithm without assessment of potential artifacts on the parametrization and transferability of effective force fields are discussed.
Publisher: American Chemical Society (ACS)
Date: 14-08-2014
DOI: 10.1021/LA501715H
Abstract: The peptides AM1 and Lac21E self-organize into switchable films at an air-water interface. In an earlier study, it was proposed that both AM1 and Lac21E formed monolayers of α-helical peptides based on consistency with neutron reflectivity data. In this article, molecular dynamics simulations of assemblies of helical and nonhelical AM1 and Lac21E at an air-water interface suggest some tendency for the peptides to spontaneously adopt an α-helical conformation. However, irrespective of the structure of the peptides, the simulations reproduced not only the structural properties of the films (thickness and distribution of the hydrophobic and hydrophilic amino acids) but also the experimental neutron reflectivity measurements at different contrast variations. This suggests that neutron reflectometry alone cannot be used to determine the structure of the peptides in this case. However, together with molecular dynamics simulations, it is possible to obtain a detailed understanding of peptide films at an atomic level.
Publisher: American Chemical Society (ACS)
Date: 15-11-2011
DOI: 10.1021/CT200196M
Abstract: The Automated force field Topology Builder (ATB, 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.
Publisher: American Chemical Society (ACS)
Date: 31-12-2011
DOI: 10.1021/JP110002Q
Abstract: 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.
Publisher: American Chemical Society (ACS)
Date: 18-10-2012
DOI: 10.1021/CT300675Z
Abstract: 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.
Publisher: Springer Science and Business Media LLC
Date: 13-04-2023
DOI: 10.1007/S00418-023-02191-8
Abstract: The second decade of the twenty-first century witnessed a new challenge in the handling of microscopy data. Big data, data deluge, large data, data compliance, data analytics, data integrity, data interoperability, data retention and data lifecycle are terms that have introduced themselves to the electron microscopy sciences. This is largely attributed to the booming development of new microscopy hardware tools. As a result, large digital image files with an average size of one terabyte within one single acquisition session is not uncommon nowadays, especially in the field of cryogenic electron microscopy. This brings along numerous challenges in data transfer, compute and management. In this review, we will discuss in detail the current state of international knowledge on big data in contemporary electron microscopy and how big data can be transferred, computed and managed efficiently and sustainably. Workflows, solutions, approaches and suggestions will be provided, with the ex le of the latest experiences in Australia. Finally, important principles such as data integrity, data lifetime and the FAIR and CARE principles will be considered.
Publisher: Wiley
Date: 13-10-2010
DOI: 10.1002/JCC.21396
Abstract: 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 nm(2) experiment 0.629-0.64 nm(2)), the volume per lipid (1.226 nm(3) experiment 1.229-1.232 nm(3)), 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.
Publisher: Wiley
Date: 19-11-2010
DOI: 10.1002/PROT.22636
Abstract: Atomistic molecular dynamics simulations have been used to investigate the conformational changes associated with the binding of human growth hormone (hGH) to the extracellular domains (ECD) of the human growth hormone receptor (hGHR), thereby shedding light on the mechanism of activation. It is shown that the removal of hGH from the hormone-bound receptor complex results in a counter-clockwise rotation of the twosubunits relative to each other by 30 degrees -64 degrees (average 45 degrees +/- 14 degrees), in close agreement in terms of both the magnitude and direction of the rotation with that proposed based on mutagenesis experiments. In addition to providing evidence to support a rotational activation mechanism, the simulations have enabled the nature of the interaction interfaces in both the cytokine-bound and unliganded hGHR states to be analyzed in detail.
Publisher: American Chemical Society (ACS)
Date: 03-12-2018
Location: France
Location: No location found
No related grants have been discovered for David Poger.