Effects of Cholesterol on the mechanism of fengycin, a biofungicide

Dynamics Simulations ◽

Recent Experimental Work ◽

Lateral Range

Fengycins are a class of antifungal lipopeptides synthesized by the bacteria Bacillus subtilis, commercially available as the primary component of the agricultural fungicide Serenade. They are toxic to fungi, but far less to mammalian cells. One key difference between mammalian and fungal cell membranes is the presence of cholesterol only in the former; recent experimental work showed that the presence of cholesterol reduces fengycin-induced membrane leakage. Since our previous all-atom and coarse-grained simulations suggested that aggregation of membrane-bound fengycin is central to its ability to disrupt membranes, we hypothesized that cholesterol might reduce fengycin aggregation. Here, we test this hypothesis using coarse-grained molecular dynamics simulations, with sampling enhanced via the weighted ensemble method. The results indicate that cholesterol subtly alters the size distribution for fengycin aggregates, limits the lateral range of their membrane disordering, and reduces the ability of aggregates to bend the membrane. Taken together, these phenomena may account for cholesterols' affects on fengycin activity.

Philosophical Transactions of The Royal Society A Mathematical Physical and Engineering Sciences ◽

Reaction–diffusion basis of retroviral infectivity

10.1098/rsta.2016.0148 ◽

2016 ◽

Vol 374 (2080) ◽

pp. 20160148 ◽

Cited By ~ 6

Author(s):

S. Kashif Sadiq

Keyword(s):

Chemical Reactions ◽

Membrane Surface ◽

Reaction Diffusion ◽

Coarse Graining ◽

Coarse Grained ◽

Multiscale Approach ◽

The Matrix ◽

Membrane Bound ◽

Spatio Temporal ◽

Retrovirus particle (virion) infectivity requires diffusion and clustering of multiple transmembrane envelope proteins (Env 3 ) on the virion exterior, yet is triggered by protease-dependent degradation of a partially occluding, membrane-bound Gag polyprotein lattice on the virion interior. The physical mechanism underlying such coupling is unclear and only indirectly accessible via experiment. Modelling stands to provide insight but the required spatio-temporal range far exceeds current accessibility by all-atom or even coarse-grained molecular dynamics simulations. Nor do such approaches account for chemical reactions, while conversely, reaction kinetics approaches handle neither diffusion nor clustering. Here, a recently developed multiscale approach is considered that applies an ultra-coarse-graining scheme to treat entire proteins at near-single particle resolution, but which also couples chemical reactions with diffusion and interactions. A model is developed of Env 3 molecules embedded in a truncated Gag lattice composed of membrane-bound matrix proteins linked to capsid subunits, with freely diffusing protease molecules. Simulations suggest that in the presence of Gag but in the absence of lateral lattice-forming interactions, Env 3 diffuses comparably to Gag-absent Env 3 . Initial immobility of Env 3 is conferred through lateral caging by matrix trimers vertically coupled to the underlying hexameric capsid layer. Gag cleavage by protease vertically decouples the matrix and capsid layers, induces both matrix and Env 3 diffusion, and permits Env 3 clustering. Spreading across the entire membrane surface reduces crowding, in turn, enhancing the effect and promoting infectivity. This article is part of the themed issue ‘Multiscale modelling at the physics–chemistry–biology interface’.

Molecular dynamics simulations of membrane deformation induced by the amphiphilic helices of Epsin, Sar1p and Arf1

10.1101/140970 ◽

2017 ◽

Author(s):

Zhen-lu Li

Keyword(s):

Lipid Membranes ◽

Critical Role ◽

Membrane Curvature ◽

Coarse Grained ◽

Insertion Depth ◽

Membrane Deformation ◽

Specific Distribution ◽

Amphiphilic Helix ◽

AbstractThe N-terminal amphiphilic helices of proteins Epsin, Sar1p and Arf1 play a critical role in initiating membrane deformation. We present here the study of the interactions of these amphiphilic helices with the lipid membranes by combining the all-atom and coarse-grained simulations. In the all-atom simulations, we find that the amphiphilic helices of Epsin and Sar1p have a shallower insertion depth into the membrane compared to the amphiphilic helix of Arf1, but remarkably, the amphiphilic helices of Epsin and Sar1p induce higher asymmetry in the lipid packing between the two monolayers of the membrane. The insertion depth of amphiphilic helix into the membrane is determined not only by the overall hydrophobicity but also by the specific distribution of polar and non-polar residues along the helix. To directly compare their ability of deforming the membrane, we further apply coarse-grained simulations to investigate the membranes deformation under the insertion of multiple helices. Importantly, it is found that the amphiphilic helices of Epsin and Sar1p generate a larger membrane curvature than that of Arf1, in accord with the experimental results qualitatively. These findings enhance our understanding of the molecular mechanism of the protein-driven membrane remodeling.

Coarse-grained simulation: a high-throughput computational approach to membrane proteins

Biochemical Society Transactions ◽

10.1042/bst0360027 ◽

2008 ◽

Vol 36 (1) ◽

pp. 27-32 ◽

Cited By ~ 94

Author(s):

Mark S.P. Sansom ◽

Kathryn A. Scott ◽

Peter J. Bond

Keyword(s):

Membrane Proteins ◽

Lipid Bilayer ◽

High Throughput ◽

Protein Interactions ◽

Coarse Grained ◽

Atomistic Simulations ◽

Lactose Permease ◽

Dynamics Simulations ◽

Good Agreement

An understanding of the interactions of membrane proteins with a lipid bilayer environment is central to relating their structure to their function and stability. A high-throughput approach to prediction of membrane protein interactions with a lipid bilayer based on coarse-grained Molecular Dynamics simulations is described. This method has been used to develop a database of CG simulations (coarse-grained simulations) of membrane proteins (http://sbcb.bioch.ox.ac.uk/cgdb). Comparison of CG simulations and AT simulations (atomistic simulations) of lactose permease reveals good agreement between the two methods in terms of predicted lipid headgroup contacts. Both CG and AT simulations predict considerable local bilayer deformation by the voltage sensor domain of the potassium channel KvAP.

Protein Induced Membrane Curvature in Coarse-Grained Simulations: Binding Interface, Insertion Depth and Lipid Spontaneous Curvature

Biophysical Journal ◽

10.1016/j.bpj.2021.05.029 ◽

2021 ◽

Author(s):

Taraknath Manda ◽

Saverio E. Spagnolie ◽

Anjon Audhya ◽

Qiang Cui

Keyword(s):

Membrane Curvature ◽

Coarse Grained ◽

Spontaneous Curvature ◽

Insertion Depth ◽

Induced Membrane ◽

Binding Interface ◽

Coarse Grained Simulations

Combining molecular dynamics simulations with small-angle X-ray and neutron scattering data to study multi-domain proteins in solution

10.1101/2019.12.26.888834 ◽

2019 ◽

Cited By ~ 2

Author(s):

Andreas Haahr Larsen ◽

Yong Wang ◽

Sandro Bottaro ◽

Sergei Grudinin ◽

Lise Arleth ◽

...

Keyword(s):

Molecular Dynamics ◽

Neutron Scattering ◽

Molecular Dynamics Simulations ◽

Small Angle ◽

Coarse Grained ◽

Scattering Data ◽

General Strategy ◽

X Ray ◽

AbstractMany proteins contain multiple folded domains separated by flexible linkers, and the ability to describe the structure and conformational heterogeneity of such flexible systems pushes the limits of structural biology. Using the three-domain protein TIA-1 as an example, we here combine coarse-grained molecular dynamics simulations with previously measured small-angle scattering data to study the conformation of TIA-1 in solution. We show that while the coarse-grained potential (Martini) in itself leads to too compact conformations, increasing the strength of protein-water interactions results in ensembles that are in very good agreement with experiments. We show how these ensembles can be refined further using a Bayesian/Maximum Entropy approach, and examine the robustness to errors in the energy function. In particular we find that as long as the initial simulation is relatively good, reweighting against experiments is very robust. We also study the relative information in X-ray and neutron scattering experiments and find that refining against the SAXS experiments leads to improvement in the SANS data. Our results suggest a general strategy for studying the conformation of multi-domain proteins in solution that combines coarse-grained simulations with small-angle X-ray scattering data that are generally most easy to obtain. These results may in turn be used to design further small-angle neutron scattering experiments that exploit contrast variation through 1H/2H isotope substitutions.

Gating Mechanisms during Actin Filament Elongation by Formins

10.1101/311431 ◽

2018 ◽

Author(s):

Fikret Aydin ◽

Naomi Courtemanche ◽

Thomas D. Pollard ◽

Gregory A. Voth

Keyword(s):

Molecular Dynamics ◽

Actin Filament ◽

Actin Filaments ◽

Coarse Grained ◽

Gating Mechanisms ◽

Helical Twist ◽

Two Factors ◽

Time Average ◽

ABSTRACTFormins play an important role in the polymerization of unbranched actin filaments, and particular formins slow elongation by 5-95%. We studied the interactions between actin and the FH2 domains of formins Cdc12, Bni1 and mDia1 to understand the factors underlying their different rates of polymerization. All-atom molecular dynamics simulations revealed two factors that influence actin filament elongation and correlate with the rates of elongation. First, FH2 domains can sterically block the addition of new actin subunits. Second, FH2 domains flatten the helical twist of the terminal actin subunits, making the end less favorable for subunit addition. Coarse-grained simulations over longer time scales support these conclusions. The simulations show that filaments spend time in states that either allow or block elongation. The rate of elongation is a time-average of the degree to which the formin compromises subunit addition rather than the formin-actin complex literally being in ‘open’ or ‘closed’ states.

Decoding the physical principles of two-component biomolecular phase separation

10.1101/2020.08.24.264655 ◽

2020 ◽

Author(s):

Yaojun Zhang ◽

Bin Xu ◽

Benjamin G. Weiner ◽

Yigal Meir ◽

Ned S. Wingreen

Keyword(s):

Phase Separation ◽

Coarse Grained ◽

Cellular Functions ◽

Ratio Effect ◽

Polymer Properties ◽

Binding Phase ◽

Membrane Bound ◽

Dynamics Simulations ◽

The Individual ◽

Physical Principles

Cells possess a multiplicity of non-membrane bound compartments, which form via liquid-liquid phase separation. These condensates assemble and dissolve as needed to enable central cellular functions. One important class of condensates is those composed of two associating polymer species that form one-to-one specific bonds. What are the physical principles that underlie phase separation in such systems? To address this question, we employed coarse-grained molecular dynamics simulations to examine how the phase boundaries depend on polymer valence, stoichiometry, and binding strength. We discovered a striking phenomenon – for sufficiently strong binding, phase separation is suppressed at rational polymer stoichiometries, which we termed the magic-ratio effect. We further developed an analytical dimer-gel theory that confirmed the magic-ratio effect and disentangled the individual roles of polymer properties in shaping the phase diagram. Our work provides new insights into the factors controlling the phase diagrams of biomolecular condensates, with implications for natural and synthetic systems.

Decoding the physical principles of two-component biomolecular phase separation

eLife ◽

10.7554/elife.62403 ◽

2021 ◽

Vol 10 ◽

Author(s):

Yaojun Zhang ◽

Bin Xu ◽

Benjamin G Weiner ◽

Yigal Meir ◽

Ned S Wingreen

Keyword(s):

Phase Separation ◽

Coarse Grained ◽

Cellular Functions ◽

Ratio Effect ◽

Polymer Properties ◽

Binding Phase ◽

Membrane Bound ◽

Dynamics Simulations ◽

The Individual ◽

Physical Principles

Cells possess a multiplicity of non-membrane-bound compartments, which form via liquid-liquid phase separation. These condensates assemble and dissolve as needed to enable central cellular functions. One important class of condensates is those composed of two associating polymer species that form one-to-one specific bonds. What are the physical principles that underlie phase separation in such systems? To address this question, we employed coarse-grained molecular dynamics simulations to examine how the phase boundaries depend on polymer valence, stoichiometry, and binding strength. We discovered a striking phenomenon – for sufficiently strong binding, phase separation is suppressed at rational polymer stoichiometries, which we termed the magic-ratio effect. We further developed an analytical dimer-gel theory that confirmed the magic-ratio effect and disentangled the individual roles of polymer properties in shaping the phase diagram. Our work provides new insights into the factors controlling the phase diagrams of biomolecular condensates, with implications for natural and synthetic systems.

Lipid molecules can induce an opening of membrane-facing tunnels in cytochrome P450 1A2

Physical Chemistry Chemical Physics ◽

10.1039/c6cp03692a ◽

2016 ◽

Vol 18 (44) ◽

pp. 30344-30356 ◽

Cited By ~ 16

Author(s):

Petr Jeřábek ◽

Jan Florián ◽

Václav Martínek

Keyword(s):

Molecular Dynamics ◽

Aqueous Solution ◽

Cytochrome P450 ◽

Molecular Dynamics Simulations ◽

Coarse Grained ◽

Cytochrome P450 1A2 ◽

Structure And Dynamics ◽

Human Cytochrome ◽

Membrane Bound ◽

The structure and dynamics of the membrane-bound full-length human cytochrome P450 1A2 (CYP1A2) in aqueous solution determined by coarse-grained and all-atom molecular dynamics simulations.

Mechanical and kinetic factors drive sorting of F-actin cross-linkers on bundles

Proceedings of the National Academy of Sciences ◽

10.1073/pnas.1820814116 ◽

2019 ◽

Vol 116 (33) ◽

pp. 16192-16197 ◽

Cited By ~ 5

Author(s):

Simon L. Freedman ◽

Cristian Suarez ◽

Jonathan D. Winkelman ◽

David R. Kovar ◽

Gregory A. Voth ◽

...

Keyword(s):

Growth Rates ◽

Lattice Models ◽

High Growth ◽

Coarse Grained ◽

Actin Binding ◽

Physical Parameters ◽

Actin Networks ◽

Cross Linker ◽

Recent Experimental Work

In cells, actin-binding proteins (ABPs) sort to different regions to establish F-actin networks with diverse functions, including filopodia used for cell migration and contractile rings required for cell division. Recent experimental work uncovered a competition-based mechanism that may facilitate spatial localization of ABPs: binding of a short cross-linker protein to 2 actin filaments promotes the binding of other short cross-linkers and inhibits the binding of longer cross-linkers (and vice versa). We hypothesize this sorting arises because F-actin is semiflexible and cannot bend over short distances. We develop a mathematical theory and lattice models encompassing the most important physical parameters for this process and use coarse-grained simulations with explicit cross-linkers to characterize and test our predictions. Our theory and data predict an explicit dependence of cross-linker separation on bundle polymerization rate. We perform experiments that confirm this dependence, but with an unexpected cross-over in dominance of one cross-linker at high growth rates to the other at slow growth rates, and we investigate the origin of this cross-over with further simulations. The nonequilibrium mechanism that we describe can allow cells to organize molecular material to drive biological processes, and our results can guide the choice and design of cross-linkers for engineered protein-based materials.