Parameters for Martini sterols and hopanoids based on a virtual-site description

Sterols play an essential role in modulating bilayer structure and dynamics. Coarse-grained molecular dynamics parameters for cholesterol and related molecules are available for the Martini force field and have been successfully used in multiple lipid bilayer studies. In this work, we focus on the use of virtual sites as a means of increasing the stability of cholesterol and cholesterol-like structures. We improve and extend the Martini parameterization of sterols in four different ways: 1—the cholesterol parameters were adapted to make use of virtual interaction sites, which markedly improves numerical stability; 2—cholesterol parameters were also modified to address reported shortcomings in reproduc- ing correct lipid phase behavior in mixed membranes; 3—parameters for ergosterol were created and adapted from cholesterols; and 4—parameters for the hopanoid class of bacterial polycyclic mole- cules were created, namely, for hopane, diploptene, bacteriohopanetetrol, and for their polycyclic base structure. (C) 2015Author(s).Allarticlecontent,exceptwhereotherwisenoted,islicensedunder a Creative Commons Attribution 3.0 Unported License. [http://dx.doi.org/10.1063/1.4937783

Flexible Lipid Bilayers in Implicit Solvent

A minimalist simulation model for lipid bilayers is presented. Each lipid is represented by a flexible chain of beads in implicit solvent. The hydrophobic effect is mimicked through an intermolecular pair potential localized at the ``water''/hydrocarbon tail interface. This potential guarantees realistic interfacial tensions for lipids in a bilayer geometry. Lipids self assemble into bilayer structures that display fluidity and elastic properties consistent with experimental model membrane systems. Varying molecular flexibility allows for tuning of elastic moduli and area/molecule over a range of values seen in experimental systems.Comment: 5 pages, 5 figure

Martini 3 Coarse-Grained Force Field:Small Molecules

The recent re-parametrization of the Martini coarse-grained force field, Martini 3, improved the accuracy of the model in predicting molecular packing and interactions in molecular dynamics simulations. Here, we describe how small molecules can be accurately parametrized within the Martini 3 framework and present a database of validated small molecule models. We pay particular attention to the description of aliphatic and aromatic ring-like structures, which are ubiquitous in small molecules such as solvents and drugs or in building blocks constituting macromolecules such as proteins and synthetic polymers. In Martini 3, ring-like structures are described by models that use higher resolution coarse-grained particles (small and tiny particles). As such, the present database constitutes one of the cornerstones of the calibration of the new Martini 3 small and tiny particle sizes. The models show excellent partitioning behavior and solvent properties. Miscibility trends between different bulk phases are also captured, completing the set of thermodynamic properties considered during the parametrization. We also show how the new bead sizes allow for a good representation of molecular volume, which translates into better structural properties such as stacking distances. We further present design strategies to build Martini 3 models for small molecules of increased complexity

Vibrational Spectra of a Mechanosensitive Channel

We report the simulated vibrational spectra of a mechanosensitive membrane channel in different gating states. Our results show that while linear absorption is insensitive to structural differences, linear dichroism and sum-frequency generation spectroscopies are sensitive to the orientation of the transmembrane helices, which is changing during the opening process. Linear dichroism cannot distinguish an intermediate structure from the closed structure, but sum-frequency generation can. In addition, we find that two-dimensional infrared spectroscopy can be used to distinguish all three investigated gating states of the mechanosensitive membrane channel.

Transmembrane helix dynamics of bacterial chemoreceptors supports a piston model of signalling.

Transmembrane α-helices play a key role in many receptors, transmitting a signal from one side to the other of the lipid bilayer membrane. Bacterial chemoreceptors are one of the best studied such systems, with a wealth of biophysical and mutational data indicating a key role for the TM2 helix in signalling. In particular, aromatic (Trp and Tyr) and basic (Arg) residues help to lock α-helices into a membrane. Mutants in TM2 of E. coli Tar and related chemoreceptors involving these residues implicate changes in helix location and/or orientation in signalling. We have investigated the detailed structural basis of this via high throughput coarse-grained molecular dynamics (CG-MD) of Tar TM2 and its mutants in lipid bilayers. We focus on the position (shift) and orientation (tilt, rotation) of TM2 relative to the bilayer and how these are perturbed in mutants relative to the wildtype. The simulations reveal a clear correlation between small (ca. 1.5 Å) shift in position of TM2 along the bilayer normal and downstream changes in signalling activity. Weaker correlations are seen with helix tilt, and little/none between signalling and helix twist. This analysis of relatively subtle changes was only possible because the high throughput simulation method allowed us to run large (n = 100) ensembles for substantial numbers of different helix sequences, amounting to ca. 2000 simulations in total. Overall, this analysis supports a swinging-piston model of transmembrane signalling by Tar and related chemoreceptors

Sequential Voxel-Based Leaflet Segmentation of Complex Lipid Morphologies

[Image: see text] As molecular dynamics simulations increase in complexity, new analysis tools are necessary to facilitate interpreting the results. Lipids, for instance, are known to form many complicated morphologies, because of their amphipathic nature, becoming more intricate as the particle count increases. A few lipids might form a micelle, where aggregation of tens of thousands could lead to vesicle formation. Millions of lipids comprise a cell and its organelle membranes, and are involved in processes such as neurotransmission and transfection. To study such phenomena, it is useful to have analysis tools that understand what is meant by emerging entities such as micelles and vesicles. Studying such systems at the particle level only becomes extremely tedious, counterintuitive, and computationally expensive. To address this issue, we developed a method to track all the individual lipid leaflets, allowing for easy and quick detection of topological changes at the mesoscale. By using a voxel-based approach and focusing on locality, we forego costly geometrical operations without losing important details and chronologically identify the lipid segments using the Jaccard index. Thus, we achieve a consistent sequential segmentation on a wide variety of (lipid) systems, including monolayers, bilayers, vesicles, inverted hexagonal phases, up to the membranes of a full mitochondrion. It also discriminates between adhesion and fusion of leaflets. We show that our method produces consistent results without the need for prefitting parameters, and segmentation of millions of particles can be achieved on a desktop machine

Piezo1 Forms Specific, Functionally Important Interactions with Phosphoinositides and Cholesterol

Touch, hearing, and blood pressure regulation require mechanically gated ion channels that convert mechanical stimuli into electrical currents. One such channel is Piezo1, which plays a key role in the transduction of mechanical stimuli in humans and is implicated in diseases, such as xerocytosis and lymphatic dysplasia. There is building evidence that suggests Piezo1 can be regulated by the membrane environment, with the activity of the channel determined by the local concentration of lipids, such as cholesterol and phosphoinositides. To better understand the interaction of Piezo1 with its environment, we conduct simulations of the protein in a complex mammalian bilayer containing more than 60 different lipid types together with electrophysiology and mutagenesis experiments. We find that the protein alters its local membrane composition, enriching specific lipids and forming essential binding sites for phosphoinositides and cholesterol that are functionally relevant and often related to Piezo1-mediated pathologies. We also identify a number of key structural connections between the propeller and pore domains located close to lipid-binding sites

Molecular versus excitonic disorder in individual artificial light-harvesting systems

Natural light-harvesting antennae employ a dense array of chromophores to optimize energy transport via the formation of delocalized excited states (excitons), which are critically sensitive to spatio-energetic variations of the molecular structure. Identifying the origin and impact of such variations is highly desirable for understanding and predicting functional properties yet hard to achieve due to averaging of many overlapping responses from individual systems. Here, we overcome this problem by measuring the heterogeneity of synthetic analogues of natural antennae-self-assembled molecular nanotubes-by two complementary approaches: single-nanotube photoluminescence spectroscopy and ultrafast 2D correlation. We demonstrate remarkable homogeneity of the nanotube ensemble and reveal that ultrafast (∼50 fs) modulation of the exciton frequencies governs spectral broadening. Using multiscale exciton modeling, we show that the dominance of homogeneous broadening at the exciton level results from exchange narrowing of strong static disorder found for individual molecules within the nanotube. The detailed characterization of static and dynamic disorder at the exciton as well as the molecular level presented here opens new avenues in analyzing and predicting dynamic exciton properties, such as excitation energy transport

Simulation studies of pore and domain formation in a phospholipid monolayer

Despite extensive study the phase behavior of phospholipid monolayers at an air-water interface is still not fully understood. In particular recent vibrational sum-frequency generation (VSFG) spectra of DPPC monolayers as a function of area density show a sharp transition in the order of the lipid chains at 1.10 nm(2)/molecule. This is in a region where the lateral pressure as a function of area is effectively constant. We have investigated the nature of this transition by studying the phase behavior of DPPC monolayers as a function of area density using molecular-dynamics simulations. The changes in order within the monolayer as a function of area density correlate well with the experimental signal. At 0.58 nm(2)/molecule we observe the onset of lateral separation of highly ordered and disordered lipids, indicating the coexistence of a gel-like liquid condensed and a fluidlike liquid expanded phase. At 0.97 nm(2)/molecule the monolayer ruptures, marking the onset of the liquid-gas (G) coexistence region. This is much earlier than suggested by fluorescence microscopy results and implies that at the point of rupture, the initial pores have an equilibrium size smaller than similar to500 nm in diameter. The rupture of the monolayer leads to a sharp increase in the overall lipid order that explains the sharp transition observed in the VSFG measurements. VSFG measurements thus may represent a sensitive means to determine the onset of the liquid-gas (G) coexistence region for such systems. (C) 2005 American Institute of Physics

Lipid membranes for membrane proteins

Andreas Kukol, ‘Lipid membranes for membrane proteins in Molecular Modeling of Proteins (Clifton: Humana Press/Sringer, 2015), ISBN: 978-1-4939-1464-7, e-BOOK ISBN: 978-1-4939-1465-4Peer reviewe