38 research outputs found
Creasing of flexible membranes at vanishing tension
The properties of freestanding tensionless interfaces and membranes at low bending rigidity κ are dominated by strong fluctuations and self-avoidance and are thus outside the range of standard perturbative analysis. We analyze this regime by a simple discretized, self-avoiding membrane model on a frame subject to periodic boundary conditions by use of Monte Carlo simulation and dynamically triangulated surface techniques. We find that at low bending rigidities, the membrane properties fall into three regimes: Below the collapse transition κBP it is subject to branched polymer instability where the framed surface is not defined, in a range below a threshold rigidity κc the conformational correlation function are characterized by power-law behavior with a continuously varying exponent α, 2<α≤4 and above κc, α=4 characteristic for linearized bending excitations. Response functions specific heat and area compressibility display pronounced peaks close to κc. The results may be important for the description of soft interface systems, such as microemulsions and membranes with in-plane cooperative phenomena
Computational Approaches to Explore Bacterial Toxin Entry into the Host Cell
Many bacteria secrete toxic protein complexes that modify and disrupt essential processes in the infected cell that can lead to cell death. To conduct their action, these toxins often need to cross the cell membrane and reach a specific substrate inside the cell. The investigation of these protein complexes is essential not only for understanding their biological functions but also for the rational design of targeted drug delivery vehicles that must navigate across the cell membrane to deliver their therapeutic payload. Despite the immense advances in experimental techniques, the investigations of the toxin entry mechanism have remained challenging. Computer simulations are robust complementary tools that allow for the exploration of biological processes in exceptional detail. In this review, we first highlight the strength of computational methods, with a special focus on all-atom molecular dynamics, coarse-grained, and mesoscopic models, for exploring different stages of the toxin protein entry mechanism. We then summarize recent developments that are significantly advancing our understanding, notably of the glycolipid–lectin (GL-Lect) endocytosis of bacterial Shiga and cholera toxins. The methods discussed here are also applicable to the design of membrane-penetrating nanoparticles and the study of the phenomenon of protein phase separation at the surface of the membrane. Finally, we discuss other likely routes for future development
Backmapping triangulated surfaces to coarse-grained membrane models
Many biological processes involve large-scale changes in membrane shape. Computer simulations of these processes are challenging since they occur across a wide range of spatiotemporal scales that cannot be investigated in full by any single current simulation technique. A potential solution is to combine different levels of resolution through a multiscale scheme. Here, we present a multiscale algorithm that backmaps a continuum membrane model represented as a dynamically triangulated surface (DTS) to its corresponding molecular model based on the coarse-grained (CG) Martini force field. Thus, we can use DTS simulations to equilibrate slow large-scale membrane conformational changes and then explore the local properties at CG resolution. We demonstrate the power of our method by backmapping a vesicular bud induced by binding of Shiga toxin and by transforming the membranes of an entire mitochondrion to near-atomic resolution. Our approach opens the way to whole cell simulations at molecular detail
Capturing Membrane Phase Separation by Dual Resolution Molecular Dynamics Simulations
[Image: see text] Understanding the lateral organization in plasma membranes remains an open problem and is of great interest to many researchers. Model membranes consisting of coexisting domains are commonly used as simplified models of plasma membranes. The coarse-grained (CG) Martini force field has successfully captured spontaneous separation of ternary membranes into a liquid-disordered and a liquid-ordered domain. With all-atom (AA) models, however, phase separation is much harder to achieve due to the slow underlying dynamics. To remedy this problem, here, we apply the virtual site (VS) hybrid method on a ternary membrane composed of saturated lipids, unsaturated lipids, and cholesterol to investigate the phase separation. The VS scheme couples the two membrane leaflets at CG and AA resolution. We found that the rapid phase separation reached by the CG leaflet can accelerate and guide this process in the AA leaflet
Dual Resolution Membrane Simulations Using Virtual Sites
All-atomistic (AA) and coarse-grain (CG) simulations have been successfully applied to investigate a broad range of biomolecular processes. However, the accessible time and length scales of AA simulation are limited and the specific molecular details of CG simulation are simplified. Here, we propose a virtual site (VS) based hybrid scheme that can concurrently couple AA and CG resolutions in a single membrane simulation, mitigating the shortcomings of either representation. With some adjustments to make the AA and CG force fields compatible, we demonstrate that lipid bilayer properties are well kept in our hybrid approach. Our VS hybrid method was also applied to simulate a small lipid vesicle, with the inner leaflet and interior solvent represented in AA, and the outer leaflet together with exterior solvent at the CG level. Our multiscale method opens the way to investigate biomembrane properties at increased computational efficiency, in particular applications involving large solvent filled regions
Coupling Coarse-Grained to Fine-Grained Models via Hamiltonian Replica Exchange
The energy landscape of biomolecular systems contains many local minima that are separated by high energy barriers. Sampling this landscape in molecular dynamics simulations is a challenging task, and often requires the use of enhanced sampling techniques. Here, we increase the sampling efficiency by coupling the fine-grained (FG) GROMOS force field to the coarse-grained (CG) Martini force field via the Hamiltonian replica exchange method (HREM). We tested the efficiency of this procedure using a lutein/octane system. In traditional simulations, cis-trans transitions of lutein are barely observed due to the high energy barrier separating these states. However, many of these transitions are sampled with our HREM scheme. The proposed method offers new possibilities for enhanced sampling of biomolecular conformations, making use of CG models without compromising the accuracy of the FG model
There and back again: bridging meso- and nanoscales to understand lipid vesicle patterning
We describe a complete methodology to bridge the scales between nanoscale
Molecular Dynamics and (micrometer) mesoscale Monte Carlo simulations in lipid
membranes and vesicles undergoing phase separation, in which curving molecular
species are furthermore embedded. To go from the molecular to the mesoscale, we
notably appeal to physical renormalization arguments enabling us to rigorously
infer the mesoscale interaction parameters from its molecular counterpart. We
also explain how to deal with the physical timescales at stake at the
mesoscale. Simulating the so-obtained mesoscale system enables us to
equilibrate the long wavelengths of the vesicles of interest, up to the vesicle
size. Conversely, we then backmap from the meso- to the nano- scale, which
enables us to equilibrate in turn the short wavelengths down to the molecular
length-scales. By applying our approach to the specific situation of the
patterning of a vesicle membrane, we show that macroscopic membranes can thus
be equilibrated at all length-scales in achievable computational time offering
an original strategy to address the fundamental challenge of time scale in
simulations of large bio-membrane systems
Martini 3 Coarse-Grained Force Field for Carbohydrates
The Martini 3 force field is a full re-parametrization of the Martini
coarse-grained model for biomolecular simulations. Due to the improved
interaction balance it allows for more accurate description of condensed phase
systems. In the present work we develop a consistent strategy to parametrize
carbohydrate molecules accurately within the framework of Martini 3. In
particular, we develop a canonical mapping scheme that decomposes arbitrarily
large carbohydrates into a limited number of fragments. Bead types for these
fragments have been assigned by matching physicochemical properties of mono-
and disaccharides. In addition, guidelines for assigning bonds, angles, and
dihedrals are developed. These guidelines enable a more accurate description of
carbohydrate conformations than in the Martini 2 force field. We show that
models obtained with this approach are able to accurately reproduce osmotic
pressures of carbohydrate water solutions. Furthermore, we provide evidence
that the model differentiates correctly the solubility of the poly-glucoses
dextran (water soluble) and cellulose (water insoluble, but soluble in
ionic-liquids). Finally, we demonstrate that the new building blocks can be
applied to glycolipids, being able to reproduce membrane properties and to
induce binding of peripheral membrane proteins. These test cases demonstrate
the validity and transferability of our approach
Annexins induce curvature on free-edge membranes displaying distinct morphologies
Annexins are a family of proteins characterized by their ability to bind anionic membranes in response to Ca2+-activation. They are involved in a multitude of cellular functions including vesiculation and membrane repair. Here, we investigate the effect of nine annexins (ANXA1-ANXA7, ANXA11, ANXA13) on negatively charged double supported membrane patches with free edges. We find that annexin members can be classified according to the membrane morphology they induce and matching a dendrogam of the annexin family based on full amino acid sequences. ANXA1 and ANXA2 induce membrane folding and blebbing initiated from membrane structural defects inside patches while ANXA6 induces membrane folding originating both from defects and from the membrane edges. ANXA4 and ANXA5 induce cooperative roll-up of the membrane starting from free edges, producing large rolls. In contrast, ANXA3 and ANXA13 roll the membrane in a fragmented manner producing multiple thin rolls. In addition to rolling, ANXA7 and ANXA11 are characterized by their ability to form fluid lenses localized between the membrane leaflets. A shared feature necessary for generating these morphologies is the ability to induce membrane curvature on free edged anionic membranes. Consequently, induction of membrane curvature may be a significant property of the annexin protein family that is important for their function