scholarly journals Seipin accumulates and traps diacylglycerols and triglycerides in its ring-like structure

2020 ◽  
Author(s):  
Valeria Zoni ◽  
Wataru Shinoda ◽  
Stefano Vanni
Keyword(s):  
Molecular Dynamics ◽  
Endoplasmic Reticulum ◽  
Molecular Dynamics Simulations ◽  
Lipid Droplets ◽  
Neutral Lipids ◽  
Health Concern ◽  
Intracellular Organelles ◽  
Dynamics Simulations ◽  
Precise Role

AbstractLipid droplets (LD) are intracellular organelles responsible for lipid storage, and they emerge from the endoplasmic reticulum (ER) upon the accumulation of neutral lipids, mostly triglycerides (TG), between the two leaflets of the ER membrane. LD biogenesis takes place at ER sites that are marked by the protein seipin, which subsequently recruits additional proteins to catalyse LD formation. Deletion of seipin, however, does not abolish LD biogenesis, and its precise role in controlling LD assembly remains unclear. Here we use molecular dynamics simulations to investigate the molecular mechanism through which seipin promotes LD formation. We find that seipin clusters TG molecules inside its unconventional ring-like oligomeric structure, and that both its luminal and transmembrane regions contribute to this process. Diacylglycerol, the precursor of TG, also clusters inside the seipin oligomer, in turn promoting TG accumulation. Our results suggest that seipin remodels the membrane of specific ER sites to prime them for LD biogenesis.Significance statementMetabolic disorders related to aberrant fat accumulation, including lipodystrophy and obesity, are a particularly serious health concern. In cells, fat accumulates in intracellular organelles, named lipid droplets (LDs). LDs form in the endoplasmic reticulum, where triglycerides, the most abundant form of fat, is produced. The Bernardinelli-Seip congenital lipodystrophy type 2 protein, seipin, has been identified as a key regulator of LD formation, but its mechanism of action remains debated and its molecular details mostly obscure. Here, we use molecular dynamics simulations to investigate the mechanism of seipin. We find that seipin can cluster and trap both triglycerides and its precursor, diacylglycerol. Our results suggest that seipin organizes the lipid composition of specific ER sites to prime them for LD biogenesis.

scholarly journals Seipin accumulates and traps diacylglycerols and triglycerides in its ring-like structure

2021 ◽  
Vol 118 (10) ◽  
pp. e2017205118
Author(s):  
Valeria Zoni ◽  
Rasha Khaddaj ◽  
Ivan Lukmantara ◽  
Wataru Shinoda ◽  
Hongyuan Yang ◽  
...  
Keyword(s):  
Molecular Dynamics ◽  
Endoplasmic Reticulum ◽  
Lipid Droplets ◽  
Neutral Lipids ◽  
Oligomeric Structure ◽  
Hydrophobic Residues ◽  
Intracellular Organelles ◽  
Transmembrane Regions ◽  
Dynamics Simulations ◽  
Precise Role

Lipid droplets (LDs) are intracellular organelles responsible for lipid storage, and they emerge from the endoplasmic reticulum (ER) upon the accumulation of neutral lipids, mostly triglycerides (TG), between the two leaflets of the ER membrane. LD biogenesis takes place at ER sites that are marked by the protein seipin, which subsequently recruits additional proteins to catalyze LD formation. Deletion of seipin, however, does not abolish LD biogenesis, and its precise role in controlling LD assembly remains unclear. Here, we use molecular dynamics simulations to investigate the molecular mechanism through which seipin promotes LD formation. We find that seipin clusters TG, as well as its precursor diacylglycerol, inside its unconventional ring-like oligomeric structure and that both its luminal and transmembrane regions contribute to this process. This mechanism is abolished upon mutations of polar residues involved in protein–TG interactions into hydrophobic residues. Our results suggest that seipin remodels the membrane of specific ER sites to prime them for LD biogenesis.

Computational studies on horseshoe shape pocket of human orexin receptor type 2 and boat conformation of suvorexant by molecular dynamics simulations

2018 ◽  
Vol 92 (1) ◽  
pp. 1221-1231 ◽  
Author(s):  
Qifeng Bai ◽  
Horacio Pérez-Sánchez ◽  
Zhuoyu Shi ◽  
Lanlan Li ◽  
Danfeng Shi ◽  
...  
Keyword(s):  
Molecular Dynamics ◽  
Molecular Dynamics Simulations ◽  
Receptor Type ◽  
Boat Conformation ◽  
Computational Studies ◽  
Dynamics Simulations

scholarly journals Amylin–Aβ oligomers at atomic resolution using molecular dynamics simulations: a link between Type 2 diabetes and Alzheimer's disease

2016 ◽  
Vol 18 (4) ◽  
pp. 2330-2338 ◽  
Author(s):  
Michal Baram ◽  
Yoav Atsmon-Raz ◽  
Buyong Ma ◽  
Ruth Nussinov ◽  
Yifat Miller
Keyword(s):  
Alzheimer’S Disease ◽  
Type 2 Diabetes ◽  
Alzheimer's Disease ◽  
Molecular Dynamics ◽  
Molecular Dynamics Simulations ◽  
Single Layer ◽  
Atomic Resolution ◽  
Aβ Oligomers ◽  
Dynamics Simulations

Aβ1–42 oligomers prefer to interact with Amylin1–37 oligomers to form single layer conformations.

scholarly journals Exchange of water for sterol underlies sterol egress from a StARkin domain

eLife ◽  
2019 ◽  
Vol 8 ◽  
Author(s):  
George Khelashvili ◽  
Neha Chauhan ◽  
Kalpana Pandey ◽  
David Eliezer ◽  
Anant K Menon
Keyword(s):  
Molecular Dynamics ◽  
Endoplasmic Reticulum ◽  
Membrane Proteins ◽  
Molecular Dynamics Simulations ◽  
Large Scale ◽  
Binding Pocket ◽  
Yeast Cells ◽  
Endoplasmic Reticulum Membrane ◽  
Polar Residues ◽  
Dynamics Simulations

Previously we identified Lam/GramD1 proteins, a family of endoplasmic reticulum membrane proteins with sterol-binding StARkin domains that are implicated in intracellular sterol homeostasis. Here, we show how these proteins exchange sterol molecules with membranes. An aperture at one end of the StARkin domain enables sterol to enter/exit the binding pocket. Strikingly, the wall of the pocket is longitudinally fractured, exposing bound sterol to solvent. Large-scale atomistic molecular dynamics simulations reveal that sterol egress involves widening of the fracture, penetration of water into the cavity, and consequent destabilization of the bound sterol. The simulations identify polar residues along the fracture that are important for sterol release. Their replacement with alanine affects the ability of the StARkin domain to bind sterol, catalyze inter-vesicular sterol exchange and alleviate the nystatin-sensitivity of lam2Δ yeast cells. These data suggest an unprecedented, water-controlled mechanism of sterol discharge from a StARkin domain.

scholarly journals Active-site protein dynamics and solvent accessibility in nativeAchromobacter cycloclastescopper nitrite reductase

IUCrJ ◽  
2017 ◽  
Vol 4 (4) ◽  
pp. 495-505 ◽  
Author(s):  
Kakali Sen ◽  
Sam Horrell ◽  
Demet Kekilli ◽  
Chin W. Yong ◽  
Thomas W. Keal ◽  
...  
Keyword(s):  
Molecular Dynamics ◽  
Molecular Dynamics Simulations ◽  
Protein Dynamics ◽  
Nitrite Reductase ◽  
Active Site ◽  
Solvent Accessibility ◽  
Nitrite Reduction ◽  
Protonation State ◽  
Dynamics Simulations

Microbial nitrite reductases are denitrifying enzymes that are a major component of the global nitrogen cycle. Multiple structures measured from one crystal (MSOX data) of copper nitrite reductase at 240 K, together with molecular-dynamics simulations, have revealed protein dynamics at the type 2 copper site that are significant for its catalytic properties and for the entry and exit of solvent or ligands to and from the active site. Molecular-dynamics simulations were performed using different protonation states of the key catalytic residues (AspCATand HisCAT) involved in the nitrite-reduction mechanism of this enzyme. Taken together, the crystal structures and simulations show that the AspCATprotonation state strongly influences the active-site solvent accessibility, while the dynamics of the active-site `capping residue' (IleCAT), a determinant of ligand binding, are influenced both by temperature and by the protonation state of AspCAT. A previously unobserved conformation of IleCATis seen in the elevated temperature series compared with 100 K structures. DFT calculations also show that the loss of a bound water ligand at the active site during the MSOX series is consistent with reduction of the type 2 Cu atom.

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 Targeting N-Terminal Human Maltase-Glucoamylase to Unravel Possible Inhibitors Using Molecular Docking, Molecular Dynamics Simulations, and Adaptive Steered Molecular Dynamics Simulations

2021 ◽  
Vol 9 ◽  
Author(s):  
Shitao Zhang ◽  
Yi Wang ◽  
Lu Han ◽  
Xueqi Fu ◽  
Song Wang ◽  
...  
Keyword(s):  
Type 2 Diabetes ◽  
Molecular Dynamics ◽  
Molecular Dynamics Simulations ◽  
Md Simulations ◽  
Steered Molecular Dynamics ◽  
Glucosidase Inhibitors ◽  
Dynamics Simulations ◽  
Multiple Drugs ◽  
Loop 2

There are multiple drugs for the treatment of type 2 diabetes, including traditional sulfonylureas biguanides, glinides, thiazolidinediones, α-glucosidase inhibitors, glucagon-like peptide-1 (GLP-1) receptor agonists, dipeptidyl peptidase IV (DPP-4) inhibitors, and sodium-glucose cotransporter 2 (SGLT2) inhibitors. α-Glucosidase inhibitors have been used to control postprandial glucose levels caused by type 2 diabetes since 1990. α-Glucosidases are rather crucial in the human metabolic system and are principally found in families 13 and 31. Maltase-glucoamylase (MGAM) belongs to glycoside hydrolase family 31. The main function of MGAM is to digest terminal starch products left after the enzymatic action of α-amylase; hence, MGAM becomes an efficient drug target for insulin resistance. In order to explore the conformational changes in the active pocket and unbinding pathway for NtMGAM, molecular dynamics (MD) simulations and adaptive steered molecular dynamics (ASMD) simulations were performed for two NtMGAM-inhibitor [de-O-sulfonated kotalanol (DSK) and acarbose] complexes. MD simulations indicated that DSK bound to NtMGAM may influence two domains (inserted loop 1 and inserted loop 2) by interfering with the spiralization of residue 497–499. The flexibility of inserted loop 1 and inserted loop 2 can influence the volume of the active pocket of NtMGAM, which can affect the binding progress for DSK to NtMGAM. ASMD simulations showed that compared to acarbose, DSK escaped from NtMGAM easily with lower energy. Asp542 is an important residue on the bottleneck of the active pocket of NtMGAM and could generate hydrogen bonds with DSK continuously. Our theoretical results may provide some useful clues for designing new α-glucosidase inhibitors to treat type 2 diabetes.

scholarly journals Mechanism of lipid droplet formation by the yeast Sei1/Ldb16 Seipin complex

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Yoel A. Klug ◽  
Justin C. Deme ◽  
Robin A. Corey ◽  
Mike F. Renne ◽  
Phillip J. Stansfeld ◽  
...  
Keyword(s):  
Molecular Dynamics ◽  
Endoplasmic Reticulum ◽  
Molecular Dynamics Simulation ◽  
Membrane Protein ◽  
Lipid Droplet ◽  
Lipid Droplets ◽  
Neutral Lipids ◽  
Dynamics Simulation ◽  
Transmembrane Segments ◽  
Lipid Droplet Formation

AbstractLipid droplets (LDs) are universal lipid storage organelles with a core of neutral lipids, such as triacylglycerols, surrounded by a phospholipid monolayer. This unique architecture is generated during LD biogenesis at endoplasmic reticulum (ER) sites marked by Seipin, a conserved membrane protein mutated in lipodystrophy. Here structural, biochemical and molecular dynamics simulation approaches reveal the mechanism of LD formation by the yeast Seipin Sei1 and its membrane partner Ldb16. We show that Sei1 luminal domain assembles a homooligomeric ring, which, in contrast to other Seipins, is unable to concentrate triacylglycerol. Instead, Sei1 positions Ldb16, which concentrates triacylglycerol within the Sei1 ring through critical hydroxyl residues. Triacylglycerol recruitment to the complex is further promoted by Sei1 transmembrane segments, which also control Ldb16 stability. Thus, we propose that LD assembly by the Sei1/Ldb16 complex, and likely other Seipins, requires sequential triacylglycerol-concentrating steps via distinct elements in the ER membrane and lumen.

Structural properties of short glucagon-like peptide-1 in various solvents investigated by molecular dynamics simulations

2017 ◽  
Vol 16 (08) ◽  
pp. 1750071
Author(s):  
Hong-Yu Cao ◽  
Wei Guo ◽  
Ya-Xian Yu ◽  
Hong-Lei Wang ◽  
Qian Tang ◽  
...  
Keyword(s):  
Molecular Dynamics ◽  
Molecular Dynamics Simulations ◽  
Ph Value ◽  
High Resolution Structure ◽  
Glucagon Like Peptide ◽  
Glucagon Like Peptide 1 ◽  
Dynamics Simulations ◽  
The Relationship ◽  
Resolution Structure

It has been reported that short glucagon-like peptide-1 (sGLP-1), one of glucagon-like peptide 1 (GLP-1) analogues, has the same effect in treating type 2 diabetes mellitus (T2DM) as GLP-1 with increased half-life in human body. Although the high-resolution structure of complex of GLP-1 and its receptor has been achieved, the relationship between the structure of GLP-1 before recognition and its final function is still not clear. As for sGLP-1, few studies attempt to investigate the influences of different conditions on its structure. In present paper, molecular dynamics simulations were applied to explore molecular details of sGLP-1 under various environments. The results demonstrated that in low pH value solvent, the additional helical residue of Pro6 and the flexible N-terminal cannot keep [Formula: see text] helix biological conformation. At pH 3, the structure has undergone significant changes, resulting in the shortest helical length. Further studies showed that protonation states of Glu21 mainly determined the secondary structure of sGLP-1 when pH values increased from 3 to 7. Interestingly, with ions concentration varying from 0.18% to 0.72%, the fluctuating trend of backbone RMSDs is consistent with that of [Formula: see text] helix structure of sGLP-1. The structure of sGLP-1 had less helix content and became more flexible when temperatures increased in the range from 305[Formula: see text]K to 320[Formula: see text]K. Meanwhile, in mixtures of water and 2,2,2-trifluoroethanol (TFE) sGLP-1 showed a rigid structure with an additional helical residue (Pro6) at the N-terminal of original helix content.

scholarly journals Global Fold of Human Cannabinoid Type 2 Receptor Probed by Solid-State NMR and Molecular Dynamics Simulations

2015 ◽  
Vol 108 (2) ◽  
pp. 251a
Author(s):  
Tomohiro Kimura ◽  
Krishna Vukoti ◽  
Diane L. Lynch ◽  
Dow P. Hurst ◽  
Alan Grossfield ◽  
...  
Keyword(s):  
Molecular Dynamics ◽  
Solid State ◽  
Molecular Dynamics Simulations ◽  
Solid State Nmr ◽  
Global Fold ◽  
Dynamics Simulations
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