27 research outputs found
CRC 1114 - Report Membrane Deformation by N-BAR Proteins: Extraction of membrane geometry and protein diffusion characteristics from MD simulations
We describe simulations of Proteins and artificial pseudo-molecules
interacting and shaping lipid bilayer membranes. We extract protein diffusion
Parameters, membrane deformation profiles and the elastic properties of the
used membrane models in preparation of calculations based on a large scale
continuum model
Interaction between antimicrobial peptides and non-lipid components in the bacterial outer envelope
Antimicrobial peptides (AMPs) offer advantages over conventional antibiotics; for example, bacteria develop resistance to a lesser extent to AMPs than to small-molecule antibiotics. The interaction of the AMPs with the liposaccharide (LPS) layer of the gram-negative bacteria cell envelope is not well understood. I constructed a MARTINI model of a gram-negative bacterial outer membrane interacting with the AMP Magainin 2. In a 20 μs MD simulation, the AMP diffused to the LPS layer of the cell envelope and remained there, suggesting interactions between the Magainin 2 and the LPS layer causing the AMP to concentrate at that position. Furthermore, the free energy profile for the insertion of the Magainin 2 into the membrane was calculated using umbrella sampling, which showed that the AMP positioned such that the cationic sidechains of the AMP coordinated to the negatively charged phosphate groups of the LPS layer. These simulations indicate that AMPs partition into the LPS layer of a bacterial membrane
Domain Rearrangement and Denaturation in Ebola Virus Protein VP40
The VP40 protein plays a critical role in coordinating the virion assembly, budding, and replication of the Ebola virus. Efforts have been made in recent years to understand various aspects of VP40 structure, dynamics, and function such as assembly of the protein and its roles in virus replication and penetration of the protein into the plasma membrane. A major conformational transformation is necessary for VP40 to form some of its oligomeric structures and to perform various functions. This conformational change from a compact structure with the N-terminal domain (NTD) and C-terminal domain (CTD) closely associated involves a dissociation or springing-out of the CTD from the NTD. We perform investigations using computational molecular dynamics simulations as well as knowledge-based Monte Carlo simulations. We find that a sharp springing of the CTD from the NTD in a free VP40 protein cannot occur solely by random thermal fluctuations without intermediate oligomerized segments, and therefore is likely triggered by additional molecular events
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
Computational Modeling of Realistic Cell Membranes
Cell membranes contain a large variety of lipid types and are crowded with proteins, endowing them with the plasticity needed to fulfill their key roles in cell functioning. The compositional complexity of cellular membranes gives rise to a heterogeneous lateral organization, which is still poorly understood. Computational models, in particular molecular dynamics simulations and related techniques, have provided important insight into the organizational principles of cell membranes over the past decades. Now, we are witnessing a transition from simulations of simpler membrane models to multicomponent systems, culminating in realistic models of an increasing variety of cell types and organelles. Here, we review the state of the art in the field of realistic membrane simulations and discuss the current limitations and challenges ahead
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
A Data-Driven Dimensionality Reduction Approach to Compare and Classify Lipid Force Fields
Molecular dynamics simulations of all-atom and coarse-grained lipid bilayer models are increasingly used to obtain useful insights for understanding the structural dynamics of these assemblies. In this context, one crucial point concerns the comparison of the performance and accuracy of classical force fields (FFs), which sometimes remains elusive. To date, the assessments performed on different classical potentials are mostly based on the comparison with experimental observables, which typically regard average properties. However, local differences of the structure and dynamics, which are poorly captured by average measurements, can make a difference, but these are nontrivial to catch. Here, we propose an agnostic way to compare different FFs at different resolutions (atomistic, united-atom, and coarse-grained), by means of a high-dimensional similarity metrics built on the framework of Smooth Overlap of Atomic Position (SOAP). We compare and classify a set of 13 FFs, modeling 1-palmitoyl-2-oleoyl-sn-glycero-3-phosphocholine (POPC) bilayers. Our SOAP kernel-based metrics allows us to compare, discriminate, and correlate different FFs at different model resolutions in an unbiased, high-dimensional way. This also captures differences between FFs in modeling nonaverage events (originating from local transitions), for example, the liquid-to-gel phase transition in dipalmitoylphosphatidylcholine (DPPC) bilayers, for which our metrics allows us to identify nucleation centers for the phase transition, highlighting some intrinsic resolution limitations in implicit versus explicit solvent FFs
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
Two decades of Martini:Better beads, broader scope
The Martini model, a coarse-grained force field for molecular dynamics simulations, has been around for nearly two decades. Originally developed for lipid-based systems by the groups of Marrink and Tieleman, the Martini model has over the years been extended as a community effort to the current level of a general-purpose force field. Apart from the obvious benefit of a reduction in computational cost, the popularity of the model is largely due to the systematic yet intuitive building-block approach that underlies the model, as well as the open nature of the development and its continuous validation. The easy implementation in the widely used Gromacs software suite has also been instrumental. Since its conception in 2002, the Martini model underwent a gradual refinement of the bead interactions and a widening scope of applications. In this review, we look back at this development, culminating with the release of the Martini 3 version in 2021. The power of the model is illustrated with key examples of recent important findings in biological and material sciences enabled with Martini, as well as examples from areas where coarse-grained resolution is essential, namely high-throughput applications, systems with large complexity, and simulations approaching the scale of whole cells. This article is categorized under: Software > Molecular Modeling Molecular and Statistical Mechanics > Molecular Dynamics and Monte-Carlo Methods Structure and Mechanism > Computational Materials Science Structure and Mechanism > Computational Biochemistry and Biophysics
Cardiolipin occupancy profiles of YidC paralogs reveal the significance of respective TM2 helix residues in determining paralog-specific phenotypes
YidC belongs to an evolutionarily conserved family of insertases, YidC/Oxa1/Alb3, in bacteria, mitochondria, and chloroplasts, respectively. Unlike Gram-negative bacteria, Gram-positives including Streptococcus mutans harbor two paralogs of YidC. The mechanism for paralog-specific phenotypes of bacterial YidC1 versus YidC2 has been partially attributed to the differences in their cytoplasmic domains. However, we previously identified a W138R gain-of-function mutation in the YidC1 transmembrane helix 2. YidC1W138R mostly phenocopied YidC2, yet the mechanism remained unknown. Primary sequence comparison of streptococcal YidCs led us to identify and mutate the YidC1W138 analog, YidC2S152 to W/A, which resulted in a loss of YidC2- and acquisition of YidC1-like phenotype. The predicted lipid-facing side chains of YidC1W138/YidC2S152 led us to propose a role for membrane phospholipids in specific-residue dependent phenotypes of S. mutans YidC paralogs. Cardiolipin (CL), a prevalent phospholipid in the S. mutans cytoplasmic membrane during acid stress, is encoded by a single gene, cls. We show a concerted mechanism for cardiolipin and YidC2 under acid stress based on similarly increased promoter activities and similar elimination phenotypes. Using coarse grain molecular dynamics simulations with the Martini2.2 Forcefield, YidC1 and YidC2 wild-type and mutant interactions with CL were assessed in silico. We observed substantially increased CL interaction in dimeric versus monomeric proteins, and variable CL occupancy in YidC1 and YidC2 mutant constructs that mimicked characteristics of the other wild-type paralog. Hence, paralog-specific amino acid- CL interactions contribute to YidC1 and YidC2-associated phenotypes that can be exchanged by point mutation at positions 138 or 152, respectively