Simulated Dynamics of Glycans on Ligand-Binding Domain of NMDA Receptors Reveals Strong Dynamic Coupling between Glycans and Protein Core

Sinitskiy, Anton V.; Pande, Vijay S.

doi:10.1021/acs.jctc.7b00817

Cited by 18 publications

(36 citation statements)

References 67 publications

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“…However, they converged to the different states (Glycan88 and Glycan396 converge to state B, Glycan240 and Glycan341 converge to state A), while they still can change between different states due to the lower energy barrier (Supporting Information Figure S6). Hence, the sampled conformations of glycan is also affected by its surrounding residues, consistent with previous study …”

Section: Resultssupporting

confidence: 91%

“…CETP‐G adopts a more stretched shape with higher hydrophobic and hydrophilic SASA of N‐terminal oscillating with larger amplitude compared to CETP‐N. Furthermore, the glycans mainly 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, consistent with previous MD results (strong dynamic coupling between glycans and protein core) …”

Section: Resultssupporting

confidence: 90%

“…Relative to CETP‐N (Supporting Information Figure S1), missed (C1 S2 K3 G4) and mutated residues (C131A N88D N240D N341D) were reversed by Discovery studio client package . The conformational sampling of glycans is time‐consuming due to high energy barriers associated with the rotation of glycosidic‐bonds . To avoid high computational costs and obtain a universal model, the pentasaccharide core part of N‐linked glycan (Man3GlcNAc2) determining the main movement of glycans was used to construct CETP‐G (Supporting Information Figure S1), via the online tool (http://www.glycosciences.de/modeling/glyprot/php/main.php).…”

Section: Methodsmentioning

confidence: 99%

“…To avoid high computational costs and obtain a universal model, the pentasaccharide core part of N‐linked glycan (Man3GlcNAc2) determining the main movement of glycans was used to construct CETP‐G (Supporting Information Figure S1), via the online tool (http://www.glycosciences.de/modeling/glyprot/php/main.php). Similar glycan Man3GlcNAc2, Man5GlcNAc2, and Man8GlcNAc2 have been widely applied in previous works . To study the state of CETP before the entrance of lipids and exclude the excrescent effects of lipids on CETP structure, all the hetero‐atoms were removed.…”

Section: Methodsmentioning

confidence: 99%

“…25 The conformational sampling of glycans is time-consuming due to high energy barriers associated with the rotation of glycosidic-bonds. 26 To avoid high computational costs and obtain a universal model, the pentasaccharide core part of N-linked glycan (Man3GlcNAc2) determining the main movement of glycans was used to construct CETP-G (Supporting Information Figure S1), via the online tool (http://www.glycosciences.de/ modeling/glyprot/php/main.php). 27 Similar glycan Man3GlcNAc2, Man5GlcNAc2, and Man8GlcNAc2 have been widely applied in previous works.…”

Section: Simulation Systemmentioning

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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Section: Resultssupporting

confidence: 91%

Section: Resultssupporting

confidence: 90%

Section: Methodsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Section: Simulation Systemmentioning

confidence: 99%

See 3 more Smart Citations

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

et al. 2018

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Computational structure‐based drug design: Predicting target flexibility

Iglesias¹,

Saen‐oon²,

Soliva³

et al. 2018

WIREs Comput Mol Sci

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The role of molecular modeling in drug design has experienced a significant revamp in the last decade. The increase in computational resources and molecular models, along with software developments, is finally introducing a competitive advantage in early phases of drug discovery. Medium and small companies with strong focus on computational chemistry are being created, some of them having introduced important leads in drug design pipelines. An important source for this success is the extraordinary development of faster and more efficient techniques for describing flexibility in three‐dimensional structural molecular modeling. At different levels, from docking techniques to atomistic molecular dynamics, conformational sampling between receptor and drug results in improved predictions, such as screening enrichment, discovery of transient cavities, etc. In this review article we perform an extensive analysis of these modeling techniques, dividing them into high and low throughput, and emphasizing in their application to drug design studies. We finalize the review with a section describing our Monte Carlo method, PELE, recently highlighted as an outstanding advance in an international blind competition and industrial benchmarks. This article is categorized under: Structure and Mechanism > Computational Biochemistry and Biophysics Software > Molecular Modeling

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Computer Simulations Predict High Structural Heterogeneity of Functional State of NMDA Receptors

Sinitskiy

Pande

2018

Biophysical Journal

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N-methyl-D-aspartate receptors (NMDARs)-i.e., transmembrane proteins expressed in neurons-play a central role in the molecular mechanisms of learning and memory formation. It is unclear how the known atomic structures of NMDARs determined by x-ray crystallography and electron cryomicroscopy (18 published Protein Data Bank entries) relate to the functional states of NMDARs inferred from electrophysiological recordings (multiple closed, open, preopen, etc. states). We address this problem by using molecular dynamics simulations at atomic resolution, a method successfully applied in the past to much smaller biomolecules. Our simulations predict that several conformations of NMDARs with experimentally determined geometries, including four "nonactive" electron cryomicroscopy structures, rapidly interconvert on submicrosecond timescales and therefore may correspond to the same functional state of the receptor (specifically, one of the closed states). This conclusion is not trivial because these conformational transitions involve changes in certain interatomic distances as large as tens of Å. The simulations also predict differences in the conformational dynamics of the apo and holo (i.e., agonist and coagonist bound) forms of the receptor on the microsecond timescale. To our knowledge, five new conformations of NMDARs, with geometries joining various features from different known experimental structures, are also predicted by the model. The main limitation of this work stems from its limited sampling (30 μs of aggregate length of molecular dynamics trajectories). Though this level significantly exceeds the sampling in previous simulations of parts of NMDARs, it is still much lower than the sampling recently achieved for smaller biomolecules (up to a few milliseconds), thus precluding, in particular, the observation of transitions between different functional states of NMDARs. Despite this limitation, such computational predictions may guide further experimental studies on the structure, dynamics, and function of NMDARs, for example by suggesting optimal locations of spectroscopic probes. Overall, atomic resolution simulations provide, to our knowledge, a novel perspective on the structure and dynamics of NMDARs, complementing information obtained by experimental methods.

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Simulated Dynamics of Glycans on Ligand-Binding Domain of NMDA Receptors Reveals Strong Dynamic Coupling between Glycans and Protein Core

Cited by 18 publications

References 67 publications

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

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

Computational structure‐based drug design: Predicting target flexibility

Computer Simulations Predict High Structural Heterogeneity of Functional State of NMDA Receptors

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