Activation Mechanisms of αVβ3 Integrin by Binding to Fibronectin: A Computational Study

Wang, Lingyun; Pan, Di; Yan, Qi; Green, Russell; Yao, Song

doi:10.1016/j.bpj.2011.11.2541

Cited by 4 publications

(11 citation statements)

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“…Several mechanisms that had been Figure 2). The extracellular matrix domain has evolved freely during the morphing simulation [Color figure can be viewed at wileyonlinelibrary.com] described earlier [4][5][6][7][8][9][10][11][12][13][14][15][16][17][18] were examined for their feasibility (Figure 1). The best description of the observations provides a switchblade motion followed by a separation of the transmembrane helices (Figure 1, model 6).…”

Section: Discussionmentioning

confidence: 99%

Molecular dynamics simulations to the bidirectional adhesion signaling pathway of integrin α_Vβ₃

Kulke

Langel

2019

Proteins

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The bidirectional force transmission process of integrin through the cell membrane is still not well understood. Several possible mechanisms have been discussed in literature on the basis of experimental data, and in this study, we investigate these mechanisms by free and steered molecular dynamics simulations. For the first time, constant velocity pulling on the complete integrin molecule inside a dipalmitoyl‐phosphatidylcholine membrane is conducted. From the results, the most likely mechanism for inside‐out and outside‐in signaling is the switchblade model with further separation of the transmembrane helices.

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Section: Discussionmentioning

confidence: 99%

Molecular dynamics simulations to the bidirectional adhesion signaling pathway of integrin α_Vβ₃

Kulke

Langel

2019

Proteins

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“…The simulation procedure is the same as our previous works . To remove bad contacts from the initial structures, each system was minimized using 2,500 steps of steepest descent method followed by 2,500 steps of the conjugate gradient method in which the protein was constrained by a force constant of 500.0 kcal/mol‐Å 2 .…”

Section: Methodsmentioning

confidence: 99%

Deprotonation states of the two active site water molecules regulate the binding of protein phosphatase 5 with its substrate: A molecular dynamics study

Wang

Yan

2017

Protein Science

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Protein phosphatase 5 (PP5), mainly localized in human brain, can dephosphorylate tau protein whose high level of phosphorylation is related to Alzheimer's disease. Similar to other protein phosphatases, PP5 has a conserved motif in the catalytic domain that contains two binding sites for manganese (Mn ) ions. Structural data indicate that two active site water molecules, one bridging the two Mn ions and the other terminally coordinated with one of the Mn ions (Mn1), are involved in catalysis. Recently, a density functional theory study revealed that the two water molecules can be both deprotonated to keep a neutral active site for catalysis. The theoretical study gives us an insight into the catalytic mechanism of PP5, but the knowledge of how the deprotonation states of the two water molecules affect the binding of PP5 with its substrate is still lacking. To approach this problem, molecular dynamics simulations were performed to model the four possible deprotonation states. Through structural, dynamical and energetic analyses, the results demonstrate that the deprotonation states of the two water molecules affect the structure of the active site including the distance between the two Mn ions and their coordination, impact the interaction energy of residues R275, R400 and H304 which directly interact with the substrate phosphoserine, and mediate the dynamics of helix αJ which is involved in regulation of the enzyme's activity. Furthermore, the deprotonation state that is preferable for PP5 binding of its substrate has been identified. These findings could provide new design strategy for PP5 inhibitor.

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“…Wang et al also employ MD simulations to investigate the dynamic changes in the structure of the α v β 3 integrin upon binding to the protein fibronectin. 143 The model of the full extracellular segment of the receptor is built from the crystallographic structure of its complex with RGD (1L5G), the missing residues of which are reconstructed from experimental data for α IIb β 3 (3FCS) and computational modeling. The RGD peptide is replaced by modules III 9 and III 10 of fibronectin, extracted from the crystallographic structure (1FNF).…”

Section: Molecular Pharmaceuticsmentioning

confidence: 99%

“…145 The structures used in the other reviewed papers are not reduced to certain domains but simulated in whole. Addition of missing residues is reported only in the work of Wang et al, 143 where the β 3 subunit is reconstructed based on α IIb β 3 (3FCS). This makes the conclusions about the global conformational changes made in this study very precise.…”

Section: Molecular Pharmaceuticsmentioning

confidence: 99%

“…Protonation of protein residues is explicitly mentioned only by Paradise et al 141 who investigate the influence of pH. Wang et al 143 add an undefined number of sodium and chloride ions, while Dong et al 145 compensate only the total system charge with 36 Na + . Ionic strength is mimicked by 150 mM NaCl in refs 133 and 143 and 150 mM KCl in ref 134.…”

Section: Molecular Pharmaceuticsmentioning

confidence: 99%

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A Look at Receptor–Ligand Pairs for Active-Targeting Drug Delivery from Crystallographic and Molecular Dynamics Perspectives

Gocheva

Ivanova

2019

Mol. Pharmaceutics

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Optimization of the systems for active-targeting drug delivery is a pending task in view of more directed transport of the active components to neoplastic cells. One of the ways to improved performance of the drug carriers is refinement of their molecular composition, size, and specific interactions with membrane receptors. Better understanding of the latter is possible through molecular-level investigation of the process of direction of the transporters to target proteins on the surface of cells. This involves unveiling the communication between these receptors and their native ligands, which can be used as vectors for targeting the drugs. The review summarizes the current knowledge on the structure, function, and ligand binding of several most common receptors, overexpressed on various types of cancer cells, and, hence, available as potential drug delivery targets. Then, the results from molecular modeling of these proteins and ligands with atomistic equilibrium molecular dynamics simulations are recapped. The digest illustrates that the computational outcome is a valuable source of microscopic information, that accurate computational methodology is available and well mastered, and that there is much room for future developments focused on even more extensive and realistic applications in the area of targeted drug delivery.

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Activation Mechanisms of αVβ3 Integrin by Binding to Fibronectin: A Computational Study

Cited by 4 publications

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Molecular dynamics simulations to the bidirectional adhesion signaling pathway of integrin α_Vβ₃

Molecular dynamics simulations to the bidirectional adhesion signaling pathway of integrin α_Vβ₃

Deprotonation states of the two active site water molecules regulate the binding of protein phosphatase 5 with its substrate: A molecular dynamics study

A Look at Receptor–Ligand Pairs for Active-Targeting Drug Delivery from Crystallographic and Molecular Dynamics Perspectives

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Activation Mechanisms of αVβ3 Integrin by Binding to Fibronectin: A Computational Study

Cited by 4 publications

References 0 publications

Molecular dynamics simulations to the bidirectional adhesion signaling pathway of integrin αVβ3

Molecular dynamics simulations to the bidirectional adhesion signaling pathway of integrin αVβ3

Deprotonation states of the two active site water molecules regulate the binding of protein phosphatase 5 with its substrate: A molecular dynamics study

A Look at Receptor–Ligand Pairs for Active-Targeting Drug Delivery from Crystallographic and Molecular Dynamics Perspectives

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Molecular dynamics simulations to the bidirectional adhesion signaling pathway of integrin α_Vβ₃

Molecular dynamics simulations to the bidirectional adhesion signaling pathway of integrin α_Vβ₃