Large-scale molecular dynamics simulation of flow under complex structure of endothelial glycocalyx

Feng, Muye; Luo, Kai H.; Ventikos, Yiannis

doi:10.1016/j.compfluid.2018.03.014

Cited by 21 publications

(15 citation statements)

References 27 publications

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“…Details about the construction of the flow/EG system and the protocol information can be found in Refs. [25,27,28].…”

Section: Protocol Detailsmentioning

confidence: 99%

“…23 With the advent of the detailed structures and the implementation of supercomputers, a series of interesting phenomena regarding the EG layer have been discovered, and most of these findings are from our group. For example, the blood flow alters the conformation of the EG [25][26][27][28] ; the conformational changes then affect their interactions with the surrounding ions, modifying the microvascular ion transport properties. [29][30][31] However, these studies mainly focus on atomic/molecular events occurring in the ectodomain.…”

Section: Introductionmentioning

confidence: 99%

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Principal mode of Syndecan‐4 mechanotransduction for the endothelial glycocalyx is a scissor‐like dimer motion

Luo

Ventikos

2019

Acta Physiologica

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Aim Endothelial glycocalyx (EG) plays a pivotal role in a plethora of diseases, like cardiovascular and renal diseases. One hallmark function of the EG as a mechanotransducer which transmits mechanical signals into cytoplasm has been documented for decades. However, the basic question ‐ how the glycocalyx transmits the flow shear stress— is unanswered so far. Our aim is to shed light on the fundamental mode of signal transmission from flow to the endothelial cytoskeleton. Methods We conduct a series of large‐scale molecular dynamics computational experiments to investigate the dynamics of glycocalyx under varying conditions (changing blood flow velocities and shedding of glycocalyx sugar chains). Results We have identified that the main pathway of signal transmission in this system manifests as a scissors‐like motion of the Syndecan‐4 core protein. Results have suggested that the force transmitted into the cytoskeleton with an order of 10 ~ 100 pN, and the main function of sugar chains of a glycocalyx element is to protect the core proteins from severe conformational changes thereby maintaining the functionality of the EG. Conclusion This research provides a reconciling explanation for a longstanding debate about the force transmission threshold based on our findings. A new explanation has also been provided to relate the role of the EG as a mechanotransducer to its function as a microvascular barrier: the EG regulates the mechanotransduction by altering the median value and variation range of the scissor angle, and the EG governs the microvascular barrier via controlling the scissor angle which will affect the intercellular cleft.

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“…Details about the construction of the flow/EG system and the protocol information can be found in Refs. [25,27,28].…”

Section: Protocol Detailsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Principal mode of Syndecan‐4 mechanotransduction for the endothelial glycocalyx is a scissor‐like dimer motion

Luo

Ventikos

2019

Acta Physiologica

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“…Details about the set-up for the boundary conditions can be found in previous publications (16)(17)(18).…”

Section: System Constructionmentioning

confidence: 99%

Understanding endothelial glycocalyx function under flow shear stress from a molecular perspective

Luo

Ventikos

2019

BIR

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BACKGROUND: The endothelial glycocalyx plays a pivotal role in regulating blood flow, filtering blood components, sensing and transducing mechanical signals. These functions are intimately related to its dynamics at the molecular level. OBJECTIVE: The objective of this research is to establish the relationship between the functions of the endothelial glycocalyx and its dynamics at the molecular level. METHODS: To establish such a relationship, large-scale molecular dynamics simulations were undertaken to mimic the dynamics of the glycocalyx and its components in the presence of flow shear stresses. RESULTS: First, motions of the glycocalyx core protein and the pertinent subdomains were scrutinised. Threedirectional movements of the glycocalyx core protein were observed, although the flow was imposed only in the x direction. Such an observation contributes to understanding the glycocalyx redistribution as reported in experiments. Unsynchronised motion of the core protein subdomains was also spotted, which provides an alternative explanation of macroscopic phenomena. Moreover, the dynamics, rootmean-square-deviations and conformational changes of the sugar chains were investigated. Based on the findings, an alternative force transmission pathway, the role of sugar chains, and potential influence on signalling transduction pathway were proposed and discussed. CONCLUSIONS: This study relates the functions of the glycocalyx with its microscopic dynamics, which fills a knowledge gap about the links between different scales.

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“…To mimic flow, external forces in the x-direction were imposed on each oxygen atom of water molecules in the ectodomain, and the tactic was successfully practiced in previous studies. [12][13][14]21 By applying the same external force, a slip boundary between ectodomain flow and the upper membrane surface is assumed. Based on our previous findings, an external force of 0.003 fN would generate a laminar flow with a physiological bulk flow velocity.…”

Section: Biomedical Engineering Societymentioning

confidence: 99%

“…Case 3_0.003 is the base case for comparison, as it mimics a situation with blood flow velocity in a physiological range. 12,14 Figure 2a illustrates six consecutive snapshots of the height distributions of the lipid membrane upper surface in Case 3_0.003. At the instant of t = 0, the surface of the lipid membrane is rough and coarse with varying heights at different locations.…”

Section: Deformation Of Lipid Membranementioning

confidence: 99%

Membrane Deformation of Endothelial Surface Layer Interspersed with Syndecan-4: A Molecular Dynamics Study

2019

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The lipid membrane of endothelial cells plays a pivotal role in maintaining normal circulatory system functions. To investigate the response of the endothelial cell membrane to changes in vascular conditions, an atomistic model of the lipid membrane interspersed with Syndecan-4 core protein was established based on experimental observations and a series of molecular dynamics simulations were undertaken. The results show that flow results in continuous deformation of the lipid membrane, and the degree of membrane deformation is not in monotonic relationship with the environmental changes (either the changes in blood velocity or the alteration of the core protein configuration). An explanation for such non-monotonic relationship is provided, which agrees with previous experimental results. The elevation of the lipid membrane surface around the core protein of the endothelial glycocalyx was also observed, which can be mainly attributed to the Coulombic interactions between the biomolecules therein. The present study demonstrates that the blood flow can deform the lipid membrane directly via the interactions between water molecules and lipid membrane atoms thereby affecting mechanosensing; it also presents an additional force transmission pathway from the flow to the lipid membrane via the glycocalyx core protein, which complements previous mechanotransduction hypothesis.

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Large-scale molecular dynamics simulation of flow under complex structure of endothelial glycocalyx

Cited by 21 publications

References 27 publications

Principal mode of Syndecan‐4 mechanotransduction for the endothelial glycocalyx is a scissor‐like dimer motion

Principal mode of Syndecan‐4 mechanotransduction for the endothelial glycocalyx is a scissor‐like dimer motion

Understanding endothelial glycocalyx function under flow shear stress from a molecular perspective

Membrane Deformation of Endothelial Surface Layer Interspersed with Syndecan-4: A Molecular Dynamics Study

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