scholarly journals Seipin transmembrane segments critically function in triglyceride nucleation and lipid droplet budding from the membrane

2021 ◽  
Author(s):  
Siyoung Kim ◽  
Jeeyun Chung ◽  
Henning Arlt ◽  
Alexander J. Pak ◽  
Robert V. Farese ◽  
...  
Keyword(s):  
Lipid Droplets ◽  
Coarse Grained ◽  
Tail Region ◽  
Sterol Esters ◽  
Transmembrane Segments ◽  
Lipid Diffusion ◽  
Dynamics Simulations ◽  
Hydrophobic Helix ◽  
Positively Charged ◽  
Different Parts

ABSTRACTLipid droplets (LDs) are organelles formed in the endoplasmic reticulum (ER) to store triacylglycerol (TG) and sterol esters. The ER protein seipin is key for LD biogenesis. Seipin forms a cage-like structure, with each seipin monomer containing a conserved hydrophobic helix (HH) and two transmembrane (TM) segments. How the different parts of seipin function in TG nucleation and LD budding is poorly understood. Here, we utilized molecular dynamics simulations of human seipin, along with cell-based experiments, to study seipin’s functions in protein-lipid interactions, lipid diffusion, and LD maturation. All-atom (AA) simulations indicate that most seipin TM segment residues located in the phospholipid (PL) tail region of the bilayer attract TG. We also find seipin TM segments control lipid diffusion and permeation into the protein complex. Simulating larger, growing LDs with coarse-grained (CG) models, we find that the seipin TM segments form a constricted neck structure to facilitate conversion of a flat oil lens into a budding LD. Using cell experiments and simulations, we also show that conserved, positively charged residues at the end of seipin’s TM segments affect LD maturation. We propose a model in which seipin TM segments critically function in TG nucleation and LD growth.

scholarly journals Proteomic analysis of monolayer-integrated proteins on lipid droplets identifies amphipathic interfacial α-helical membrane anchors

2018 ◽  
Vol 115 (35) ◽  
pp. E8172-E8180 ◽  
Author(s):  
Camille I. Pataki ◽  
João Rodrigues ◽  
Lichao Zhang ◽  
Junyang Qian ◽  
Bradley Efron ◽  
...  
Keyword(s):  
Lipid Droplets ◽  
Coarse Grained ◽  
Structural Basis ◽  
Endoplasmic Reticulum Membrane ◽  
Membrane Surfaces ◽  
Common Motif ◽  
Cysteine Scanning Mutagenesis ◽  
Α Helix ◽  
Dynamics Simulations ◽  
Integral Proteins

Despite not spanning phospholipid bilayers, monotopic integral proteins (MIPs) play critical roles in organizing biochemical reactions on membrane surfaces. Defining the structural basis by which these proteins are anchored to membranes has been hampered by the paucity of unambiguously identified MIPs and a lack of computational tools that accurately distinguish monolayer-integrating motifs from bilayer-spanning transmembrane domains (TMDs). We used quantitative proteomics and statistical modeling to identify 87 high-confidence candidate MIPs in lipid droplets, including 21 proteins with predicted TMDs that cannot be accommodated in these monolayer-enveloped organelles. Systematic cysteine-scanning mutagenesis showed the predicted TMD of one candidate MIP, DHRS3, to be a partially buried amphipathic α-helix in both lipid droplet monolayers and the cytoplasmic leaflet of endoplasmic reticulum membrane bilayers. Coarse-grained molecular dynamics simulations support these observations, suggesting that this helix is most stable at the solvent–membrane interface. The simulations also predicted similar interfacial amphipathic helices when applied to seven additional MIPs from our dataset. Our findings suggest that interfacial helices may be a common motif by which MIPs are integrated into membranes, and provide high-throughput methods to identify and study MIPs.

scholarly journals Atomistic Molecular Dynamics Simulations of Trioleoylglycerol – Phospholipid Membrane Systems

2020 ◽  
Author(s):  
Mirza Ahmed Hammad ◽  
Hafiza Minal Akram ◽  
Muhammad Sohail Raza
Keyword(s):  
Molecular Dynamics ◽  
Molecular Dynamics Simulations ◽  
Lipid Droplets ◽  
Membrane System ◽  
Bilayer Membrane ◽  
Coarse Grained ◽  
Phospholipid Membrane ◽  
Software Suite ◽  
Future Studies ◽  
Dynamics Simulations

AbstractAdiposomes are phospholipid coated triacylglyceride particles that serve as structural models of the fat storage compartments of cells, known as lipid droplets (LDs); however, unlike LDs, they do not carry proteins. There is a deficit of available methods and experimental data regarding the internal packing of the adiposomes, and computer simulations offer a promising way to pinpoint the molecular arrangements within these structures. However, in the absence of a triacylglycerol-specific atomic forcefield, thus far, all adiposome/LD simulations have been performed with the coarse grained/united atom forcefields. Yet it is desirable to model the phospholipid/triacylglycerol interface with atomic resolution. In the present study, we first prepared a 2-monooleoylglycerol (MOG) forcefield which was then used to build a trioleoylglycerol (TOG) forcefield by the modular approach of the AMBER software suite. TOG bilayer membrane (2L) systems were modelled from two different initial conformations; TOG3 and TOG2:1. The simulations revealed that TOG2:1 is the most populated conformation in TOG membranes, irrespective of the starting conformation. Some other parameter optimizations were performed for TOG membranes based on which adiposome mimicking tetralayer membrane system (4L) was prepared with a TOG bilayer at core surrounded by two DOPC leaflets. The 4L membranes were stable throughout the simulations, however it was observed that a small amount of cations and water diffused from surface to the TOG core of the membrane. Based on these results a TAG-packing model was also developed. It is expected that the availability of MOG forcefield will equip future studies with a framework for molecular dynamics simulations of adiposomes/LDs.

scholarly journals Coarse-grained molecular dynamics simulations reveal lipid access pathways in P-glycoprotein

2018 ◽  
Vol 150 (3) ◽  
pp. 417-429 ◽  
Author(s):  
Estefania Barreto-Ojeda ◽  
Valentina Corradi ◽  
Ruo-Xu Gu ◽  
D. Peter Tieleman
Keyword(s):  
Molecular Dynamics ◽  
Molecular Dynamics Simulations ◽  
Experimental Studies ◽  
Lipid Binding ◽  
Coarse Grained ◽  
Glycoprotein P ◽  
P Glycoprotein ◽  
Dynamics Simulations ◽  
Positively Charged ◽  
Coarse Grained Molecular Dynamics

P-glycoprotein (P-gp) exports a broad range of dissimilar compounds, including drugs, lipids, and lipid-like molecules. Because of its substrate promiscuity, P-gp is a key player in the development of cancer multidrug resistance. Although P-gp is one of the most studied ABC transporters, the mechanism by which its substrates access the cavity remains unclear. In this study, we perform coarse-grained molecular dynamics simulations to explore possible lipid access pathways in the inward-facing conformation of P-gp embedded in bilayers of different lipid compositions. In the inward-facing orientation, only lipids from the lower leaflet access the cavity of the transporter. We identify positively charged residues at the portals of P-gp that favor lipid entrance to the cavity, as well as lipid-binding sites at the portals and within the cavity, which is in good agreement with previous experimental studies. This work includes several examples of lipid pathways for phosphatidylcholine and phosphatidylethanolamine lipids that help elucidate the molecular mechanism of lipid binding in P-gp.

Parameterization of Divalent Cations for Coarse-Grained Simulations

2020 ◽  
Author(s):  
Florencia Klein ◽  
Daniela Cáceres-Rojas ◽  
Monica Carrasco ◽  
Juan Carlos Tapia ◽  
Julio Caballero ◽  
...  
Keyword(s):  
Molecular Dynamics ◽  
Metal Ions ◽  
Molecular Dynamics Simulations ◽  
Divalent Cations ◽  
Computational Cost ◽  
Data Bank ◽  
Coarse Grained ◽  
Interaction Parameters ◽  
Dynamics Simulations ◽  
Dynamical Description

<p>Although molecular dynamics simulations allow for the study of interactions among virtually all biomolecular entities, metal ions still pose significant challenges to achieve an accurate structural and dynamical description of many biological assemblies. This is particularly the case for coarse-grained (CG) models. Although the reduced computational cost of CG methods often makes them the technique of choice for the study of large biomolecular systems, the parameterization of metal ions is still very crude or simply not available for the vast majority of CG- force fields. Here, we show that incorporating statistical data retrieved from the Protein Data Bank (PDB) to set specific Lennard-Jones interactions can produce structurally accurate CG molecular dynamics simulations. Using this simple approach, we provide a set of interaction parameters for Calcium, Magnesium, and Zinc ions, which cover more than 80% of the metal-bound structures reported on the PDB. Simulations performed using the SIRAH force field on several proteins and DNA systems show that using the present approach it is possible to obtain non-bonded interaction parameters that obviate the use of topological constraints. </p>

scholarly journals Solubilization of Charged Porphyrins in Interpolyelectrolyte Complexes: A Computer Study

Polymers ◽  
2021 ◽  
Vol 13 (4) ◽  
pp. 502
Author(s):  
Karel Šindelka ◽  
Zuzana Limpouchová ◽  
Karel Procházka
Keyword(s):  
Dissipative Particle Dynamics ◽  
Water Soluble ◽  
Coarse Grained ◽  
Core Shell ◽  
Computer Study ◽  
Interpolyelectrolyte Complex ◽  
The Core ◽  
Porphyrin Derivatives ◽  
Oppositely Charged ◽  
Positively Charged

Using coarse-grained dissipative particle dynamics (DPD) with explicit electrostatics, we performed (i) an extensive series of simulations of the electrostatic co-assembly of asymmetric oppositely charged copolymers composed of one (either positively or negatively charged) polyelectrolyte (PE) block A and one water-soluble block B and (ii) studied the solubilization of positively charged porphyrin derivatives (P+) in the interpolyelectrolyte complex (IPEC) cores of co-assembled nanoparticles. We studied the stoichiometric mixtures of 137 A10+B25 and 137 A10−B25 chains with moderately hydrophobic A blocks (DPD interaction parameter aAS=35) and hydrophilic B blocks (aBS=25) with 10 to 120 P+ added (aPS=39). The P+ interactions with other components were set to match literature information on their limited solubility and aggregation behavior. The study shows that the moderately soluble P+ molecules easily solubilize in IPEC cores, where they partly replace PE+ and electrostatically crosslink PE− blocks. As the large P+ rings are apt to aggregate, P+ molecules aggregate in IPEC cores. The aggregation, which starts at very low loadings, is promoted by increasing the number of P+ in the mixture. The positively charged copolymers repelled from the central part of IPEC core partially concentrate at the core-shell interface and partially escape into bulk solvent depending on the amount of P+ in the mixture and on their association number, AS. If AS is lower than the ensemble average ⟨AS⟩n, the copolymer chains released from IPEC preferentially concentrate at the core-shell interface, thus increasing AS, which approaches ⟨AS⟩n. If AS>⟨AS⟩n, they escape into the bulk solvent.

scholarly journals Variation of Interaction Zone Size For The Target Design of 2D Supramolecular Networks

2021 ◽  
Author(s):  
Łukasz Piotr Baran ◽  
Wojciech Rżysko ◽  
Dariusz Tarasewicz
Keyword(s):  
Molecular Dynamics ◽  
Molecular Dynamics Simulations ◽  
Self Assembly ◽  
The Self ◽  
Coarse Grained ◽  
Zone Size ◽  
Interaction Zone ◽  
Supramolecular Networks ◽  
Dynamics Simulations ◽  
Target Design

In this study we have performed extensive coarse-grained molecular dynamics simulations of the self-assembly of tetra-substituted molecules. We have found that such molecules are able to form a variety of...

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