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.
Cell membranes provide a selective semi-permeable barrier to the passive transport of molecules. This property differs greatly between organisms. While the cytoplasmic membrane of bacterial cells is ...highly permeable for weak acids and glycerol, yeasts can maintain large concentration gradients. Here we show that such differences can arise from the physical state of the plasma membrane. By combining stopped-flow kinetic measurements with molecular dynamics simulations, we performed a systematic analysis of the permeability of a variety of small molecules through synthetic membranes of different lipid composition to obtain detailed molecular insight into the permeation mechanisms. While membrane thickness is an important parameter for the permeability through fluid membranes, the largest differences occur when the membranes transit from the liquid-disordered to liquid-ordered and/or to gel state, which is in agreement with previous work on passive diffusion of water. By comparing our results with in vivo measurements from yeast, we conclude that the yeast membrane exists in a highly ordered and rigid state, which is comparable to synthetic saturated DPPC-sterol membranes.
Coarse-grained (CG) simulations have become an essential tool to study a large variety of biomolecular processes, exploring temporal and spatial scales inaccessible to traditional models of atomistic ...resolution. One of the major simplifications of CG models is the representation of the solvent, which is either implicit or modeled explicitly as a van der Waals particle. The effect of polarization, and thus a proper screening of interactions depending on the local environment, is absent. Given the important role of water as a ubiquitous solvent in biological systems, its treatment is crucial to the properties derived from simulation studies. Here, we parameterize a polarizable coarse-grained water model to be used in combination with the CG MARTINI force field. Using a three-bead model to represent four water molecules, we show that the orientational polarizability of real water can be effectively accounted for. This has the consequence that the dielectric screening of bulk water is reproduced. At the same time, we parameterized our new water model such that bulk water density and oil/water partitioning data remain at the same level of accuracy as for the standard MARTINI force field. We apply the new model to two cases for which current CG force fields are inadequate. First, we address the transport of ions across a lipid membrane. The computed potential of mean force shows that the ions now naturally feel the change in dielectric medium when moving from the high dielectric aqueous phase toward the low dielectric membrane interior. In the second application we consider the electroporation process of both an oil slab and a lipid bilayer. The electrostatic field drives the formation of water filled pores in both cases, following a similar mechanism as seen with atomistically detailed models.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Abstract
The detailed understanding of the binding of small molecules to proteins is the key for the development of novel drugs or to increase the acceptance of substrates by enzymes. Nowadays, ...computer-aided design of protein–ligand binding is an important tool to accomplish this task. Current approaches typically rely on high-throughput docking essays or computationally expensive atomistic molecular dynamics simulations. Here, we present an approach to use the recently re-parametrized coarse-grained Martini model to perform unbiased millisecond sampling of protein–ligand interactions of small drug-like molecules. Remarkably, we achieve high accuracy without the need of any a priori knowledge of binding pockets or pathways. Our approach is applied to a range of systems from the well-characterized T4 lysozyme over members of the GPCR family and nuclear receptors to a variety of enzymes. The presented results open the way to high-throughput screening of ligand libraries or protein mutations using the coarse-grained Martini model.
Perspective on the Martini model Marrink, Siewert J; Tieleman, D. Peter
Chemical Society reviews,
2013-Aug-21, Letnik:
42, Številka:
16
Journal Article
Recenzirano
Odprti dostop
The Martini model, a coarse-grained force field for biomolecular simulations, has found a broad range of applications since its release a decade ago. Based on a building block principle, the model ...combines speed and versatility while maintaining chemical specificity. Here we review the current state of the model. We describe recent highlights as well as shortcomings, and our ideas on the further development of the model.
Coarse-graining coming of age: a review of the first decade of the Martini force field.
Simulating realistic membrane shapes Pezeshkian, Weria; Marrink, Siewert J.
Current opinion in cell biology,
08/2021, Letnik:
71
Journal Article
Recenzirano
Odprti dostop
Biological membranes exhibit diversity in their shapes and complexity in chemical compositions that are linked to many cellular functions. These two central features of biomembranes have been the ...subject of numerous simulation studies, using a diverse range of computational techniques. Currently, the field is able to capture this complexity at increasing levels of realism and connect the microscopic view on protein–lipid interactions to cellular morphologies at the level of entire organelles. Here we highlight recent advances in this topic, identify current bottlenecks, and sketch possible ways ahead.
Molecular dynamics simulations play an increasingly important role in the rational design of (nano)-materials and in the study of biomacromolecules. However, generating input files and realistic ...starting coordinates for these simulations is a major bottleneck, especially for high throughput protocols and for complex multi-component systems. To eliminate this bottleneck, we present the polyply software suite that provides 1) a multi-scale graph matching algorithm designed to generate parameters quickly and for arbitrarily complex polymeric topologies, and 2) a generic multi-scale random walk protocol capable of setting up complex systems efficiently and independent of the target force-field or model resolution. We benchmark quality and performance of the approach by creating realistic coordinates for polymer melt simulations, single-stranded as well as circular single-stranded DNA. We further demonstrate the power of our approach by setting up a microphase-separated block copolymer system, and by generating a liquid-liquid phase separated system inside a lipid vesicle.
In molecular dynamics simulations, sufficient sampling is of key importance and a continuous challenge in the field. The coarse grain Martini force field has been widely used to enhance sampling. In ...its original implementation, this force field applied a shifted Lennard-Jones potential for the non-bonded van der Waals interactions, to avoid problems related to a relatively short cutoff. Here we investigate the use of a straight cutoff Lennard-Jones potential with potential modifiers. Together with a Verlet neighbor search algorithm, the modified potential allows the use of GPUs to accelerate the computations in Gromacs. We find that this alternative potential has little influence on most of the properties studied, including partitioning free energies, bulk liquid properties and bilayer properties. At the same time, energy conservation is kept within reasonable bounds. We conclude that the newly proposed straight cutoff approach is a viable alternative to the standard shifted potentials used in Martini, offering significant speedup even in the absence of GPUs.
Photosynthesis is regulated by a dynamic interplay between proteins, enzymes, pigments, lipids, and cofactors that takes place on a large spatio-temporal scale. Molecular dynamics (MD) simulations ...provide a powerful toolkit to investigate dynamical processes in (bio)molecular ensembles from the (sub)picosecond to the (sub)millisecond regime and from the Å to hundreds of nm length scale. Therefore, MD is well suited to address a variety of questions arising in the field of photosynthesis research. In this review, we provide an introduction to the basic concepts of MD simulations, at atomistic and coarse-grained level of resolution. Furthermore, we discuss applications of MD simulations to model photosynthetic systems of different sizes and complexity and their connection to experimental observables. Finally, we provide a brief glance on which methods provide opportunities to capture phenomena beyond the applicability of classical MD.
Ceramides draw wide attention as tumor suppressor lipids that act directly on mitochondria to trigger apoptotic cell death. However, molecular details of the underlying mechanism are largely unknown. ...Using a photoactivatable ceramide probe, we here identify the voltage-dependent anion channels VDAC1 and VDAC2 as mitochondrial ceramide binding proteins. Coarse-grain molecular dynamics simulations reveal that both channels harbor a ceramide binding site on one side of the barrel wall. This site includes a membrane-buried glutamate that mediates direct contact with the ceramide head group. Substitution or chemical modification of this residue abolishes photolabeling of both channels with the ceramide probe. Unlike VDAC1 removal, loss of VDAC2 or replacing its membrane-facing glutamate with glutamine renders human colon cancer cells largely resistant to ceramide-induced apoptosis. Collectively, our data support a role of VDAC2 as direct effector of ceramide-mediated cell death, providing a molecular framework for how ceramides exert their anti-neoplastic activity.
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