Structural features of cholesteryl ester transfer protein: A molecular dynamics simulation study

Lei, Dongsheng; Zhang, Xing; Jiang, Shengbo; Cai, Zhaodi; Rames, Matthew J.; Zhang, Lei; Ren, Gang; Zhang, Shengli

doi:10.1002/prot.24200

Cited by 26 publications

(52 citation statements)

References 41 publications

(71 reference statements)

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“…CETP directionally bound to HDL is consistent with many earlier reports, including i) a CETP-mediated net transfer of CE into VLDL34, ii) CETP bridging HDL and LDL instead of bridging two HDL or LDL particles13, iii) the distal portion of the N-terminal β-barrel domain of CETP being more flexible in solution than is indicated by its crystal structure14; and iv) MD simulations showing that the penetration of the N-terminal β-barrel domain of CETP into the HDL surface generates an opening that allows CE to access the CETP tunnel15. However, our results are inconsistent with those of other investigators who have shown that CETP binds to the edge of discoidal HDL35 via an interaction with apoA-I36, and atomistic and coarse-grained simulations of CETP–HDL interaction which have shown that the N-terminus helix-X domain of CETP penetrates deeply into the HDL particle core37.…”

Section: Discussionsupporting

confidence: 91%

HDL surface lipids mediate CETP binding as revealed by electron microscopy and molecular dynamics simulation

Zhang

Charles

Tong

et al. 2015

Sci Rep

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Cholesteryl ester transfer protein (CETP) mediates the transfer of cholesterol esters (CE) from atheroprotective high-density lipoproteins (HDL) to atherogenic low-density lipoproteins (LDL). CETP inhibition has been regarded as a promising strategy for increasing HDL levels and subsequently reducing the risk of cardiovascular diseases (CVD). Although the crystal structure of CETP is known, little is known regarding how CETP binds to HDL. Here, we investigated how various HDL-like particles interact with CETP by electron microscopy and molecular dynamics simulations. Results showed that CETP binds to HDL via hydrophobic interactions rather than protein-protein interactions. The HDL surface lipid curvature generates a hydrophobic environment, leading to CETP hydrophobic distal end interaction. This interaction is independent of other HDL components, such as apolipoproteins, cholesteryl esters and triglycerides. Thus, disrupting these hydrophobic interactions could be a new therapeutic strategy for attenuating the interaction of CETP with HDL.

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Section: Discussionsupporting

confidence: 91%

HDL surface lipids mediate CETP binding as revealed by electron microscopy and molecular dynamics simulation

Zhang

Charles

Tong

et al. 2015

Sci Rep

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“…Thus, the glycans probably play a part in modulating the CEs transfer through the hydrophobic tunnel of CETP. Flaps Ω1∼Ω6 and Helix‐X of CETP‐N and CETP‐G are indeed flexible, consistent with previous atomistic MD simulations . However, the peak RMSF values of the N‐terminal of CETP‐G are higher than those of CETP‐N, especially for the Ω4 and Ω5 flaps.…”

Section: Resultssupporting

confidence: 88%

“…This variant of MD results could attribute to the simulation time and different initial model. During our simulations, the missed (C1 S2 K3 G4) and mutated residues (C131A N88D N240D N341D) were reversed, and the bound lipids were all removed, while original crystal structure with inhibitor or lipids in previous works . Of note, both flap Ω1 and Ω2 were flexible than other flaps in CETP‐C .…”

Section: Resultsmentioning

confidence: 99%

“…Solvent‐accessible surface area (SASA) was calculated with a 1.4 Å probe radius, except the consideration of glycan SASAs. The hydrophobic and hydrophilic residues SASA were calculated to evaluate the hydrophobicity and hydrophilicity, respectively . Principal Component Analysis (PCA) was performed on each Cα atom from the MD snapshots using cpptraj module in AmberTools .…”

Section: Methodsmentioning

confidence: 99%

“…While plasma CETP has 4 potential N‐linked glycosylation sites (CETP‐G), which play an important role in the heteroexchange of CEs and TGs between lipoproteins . Up to now, most studies on CETP have only focused on the nascent structure of CETP (CETP‐N, mutated residues were reversed) and CETP‐C . Thus, little is known about the detailed structural information of CETP‐G and effect of glycans on the structure and function of CETP, as well as the accompanying modulation of CEs transfer.…”

Section: Introductionmentioning

confidence: 99%

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Role of glycans in cholesteryl ester transfer protein revealed by molecular dynamics simulation

et al. 2018

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Current cholesteryl ester transfer protein (CETP) inhibitors are designed based on the unglycosylated crystal structure, and most of them have failed to cure cardiovascular disease (CVD). It is particularly important for us to investigate the glycosylation structure of CETP (CETP-G) and effect of glycans on the structure and function of CETP. Here, we used a total of 3.0-μs molecular dynamics (MD) trajectories of nascent structure of CETP (CETP-N) and CETP-G to study their structural differentiations, to shed new light on the CETP-mediated lipid exchange. In accordance with our simulations and previous mutation studies, relative to CETP-N, CETP-G adopts a more stretched shape with higher hydrophobic and hydrophilic solvent-accessible surface area (SASA) of N-terminal oscillating with larger amplitude, in which Glycan88 provides partial assistance for CEs through the N-terminal. Glycan341 reduces the flexibility of neck flap, with the interference of CEs through the neck region. Besides, Glycan240 reduces the flexibility of Helix-X to interfere the CEs transfer. Glycan396 decreases the flexibility and increases the hydrophobic SASA of C-terminal. Overall, these glycans affect the dynamics and structure of CETP through forming H-bonds with surrounding residues, and the sampled conformations of glycan is also affected by its surrounding residues. Thus, glycans are an integral part of CETP, further studies on the CETP inhibition and treatment of CVD should fully consider the effect of glycans.

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New insight into the architecture of oxy‐anion pocket in unliganded conformation of GAT domains: A MD‐simulation study

Bairagya

Bansal

2016

Proteins

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Human Guanine Monophosphate Synthetase (hGMPS) converts XMP to GMP, and acts as a bifunctional enzyme with N-terminal "glutaminase" (GAT) and C-terminal "synthetase" domain. The enzyme is identified as a potential target for anti-cancer and immunosuppressive therapies. GAT domain of enzyme plays central role in metabolism, and contains conserved catalytic residues Cys104, His190, and Glu192. MD simulation studies on GAT domain suggest that position of oxyanion in unliganded conformation is occupied by one conserved water molecule (W1), which also stabilizes that pocket. This position is occupied by a negatively charged atom of the substrate or ligand in ligand bound crystal structures. In fact, MD simulation study of Ser75 to Val indicates that W1 conserved water molecule is stabilized by Ser75, while Thr152, and His190 also act as anchor residues to maintain appropriate architecture of oxyanion pocket through water mediated H-bond interactions. Possibly, four conserved water molecules stabilize oxyanion hole in unliganded state, but they vacate these positions when the enzyme (hGMPS)-substrate complex is formed. Thus this study not only reveals functionally important role of conserved water molecules in GAT domain, but also highlights essential role of other non-catalytic residues such as Ser75 and Thr152 in this enzymatic domain. The results from this computational study could be of interest to experimental community and provide a testable hypothesis for experimental validation. Conserved sites of water molecules near and at oxyanion hole highlight structural importance of water molecules and suggest a rethink of the conventional definition of chemical geometry of inhibitor binding site.

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Structural features of cholesteryl ester transfer protein: A molecular dynamics simulation study

Cited by 26 publications

References 41 publications

HDL surface lipids mediate CETP binding as revealed by electron microscopy and molecular dynamics simulation

HDL surface lipids mediate CETP binding as revealed by electron microscopy and molecular dynamics simulation

Role of glycans in cholesteryl ester transfer protein revealed by molecular dynamics simulation

New insight into the architecture of oxy‐anion pocket in unliganded conformation of GAT domains: A MD‐simulation study

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