Prediction of binding characteristics between von Willebrand factor and platelet glycoprotein Ibα with various mutations by molecular dynamic simulation

Goto, Shinichi; Oka, Hideki; Ayabe, Kengo; Yabushita, Hiroto; Nakayama, Masamitsu; Hasebe, Terumitsu; Yokota, Hideo; Takagi, Shu; Sano, Motoaki; Tomita, Aiko

doi:10.1016/j.thromres.2019.10.022

Cited by 10 publications

(18 citation statements)

References 47 publications

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“…The molecular dynamics simulation was done on water-soluble condition using Nanoscale Molecular Dynamics (NAMD) version 2.12 52 with Chemistry at Harvard Molecular Mechanics (CHARMM) 36 force field 53 . The position and velocity vector of each atom and water molecule were calculated in each 2.0 femto-seconds (1 × 10 −15 s) and Particle Mesh Ewald (PME) summation with a cut off length of 12 Å for the direct interactions was used for predicting long range electrostatic interaction 54 . The simulation was done with the options of rigibBonds all and the system was neutralized with NaCl in physiological condition (150 mEq/l).…”

Section: Methodsmentioning

confidence: 99%

Omega-3 fatty acid epoxides produced by PAF-AH2 in mast cells regulate pulmonary vascular remodeling

et al. 2022

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Pulmonary hypertension is a fatal rare disease that causes right heart failure by elevated pulmonary arterial resistance. There is an unmet medical need for the development of therapeutics focusing on the pulmonary vascular remodeling. Bioactive lipids produced by perivascular inflammatory cells might modulate the vascular remodeling. Here, we show that ω-3 fatty acid-derived epoxides (ω-3 epoxides) released from mast cells by PAF-AH2, an oxidized phospholipid-selective phospholipase A2, negatively regulate pulmonary hypertension. Genetic deletion of Pafah2 in mice accelerate vascular remodeling, resulting in exacerbation of hypoxic pulmonary hypertension. Treatment with ω-3 epoxides suppresses the lung fibroblast activation by inhibiting TGF-β signaling. In vivo ω-3 epoxides supplementation attenuates the progression of pulmonary hypertension in several animal models. Furthermore, whole-exome sequencing for patients with pulmonary arterial hypertension identifies two candidate pathogenic variants of Pafah2. Our findings support that the PAF-AH2-ω-3 epoxide production axis could be a promising therapeutic target for pulmonary hypertension.

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Section: Methodsmentioning

confidence: 99%

Omega-3 fatty acid epoxides produced by PAF-AH2 in mast cells regulate pulmonary vascular remodeling

et al. 2022

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“…The position coordinates and velocity vectors of all the atoms constructing the A1 domain of VWF (VWF: residues ASP(D):1269-PRO(P):1466) binding with the N-terminal domain of platelet GPIbα (GPIba: residues HIS(H):1-PRO(P):265) were solved by molecular dynamic simulation calculation as previously published. [2,33] The energetically most stable structure with a mass center distance between GPIbα and VWF of 27.3 Å was selected as the initial structure of wild-type GPIbα bound with VWF. The amino acid G233 at GPIbα in this structure was substituted by A, D, and V to provide initial binding structures with VWF.…”

Section: Molecular Dynamic (Md) Simulation Initial Structure Of Gpibα...mentioning

confidence: 99%

Physical Characteristics of von Willebrand Factor Binding with Platelet Glycoprotein Ibɑ Mutants at Residue 233 Causing Various Biological Functions

Nakayama

Goto

2022

TH Open

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Glycoprotein (GP: HIS1-PRO265) Ibα is a receptor protein expressed on the surface of the platelet. Its N-terminus domain binds with the A1 domain (ASP1269-PRO1472) of its ligand protein von Willebrand factor (VWF) and plays a unique role for platelet adhesion under blood flow conditions. Single amino acid substitutions at residue 233 from Glycine(G) to Alanine(A), Aspartic acid(D), or Valine(V) are known to cause bio-chemically distinct functional alterations known as equal, loss, and gain of function, respectively. However, the underlying physical characteristics of VWF binding with GPIbα in wild type and the three mutants exerting different biological functions are unclear. Here, we aimed to test the hypothesis: biological characteristics of macromolecules is influenced by small changes in physical parameters. The position coordinates and velocity vectors of all atoms and water molecules constructing the wild type and the three mutants of GPIbα (G233A, G233D, and G233V) bound with VWF were calculated every 2 x 10-15 sec using the CHARMM (Chemistry at HARvard Macromolecular Mechanics) force field for 9 x 10-10 sec. Six salt bridges were detected for longer than 50% of the calculation period for the wild-type model generating a non-covalent binding energy of -1096±137.6 kcal/mol. In contrast, only 4 pairs of salt bridges were observed in G233D mutant with a non-covalent binding energy of -865±139. For G233A and G233V, there were 6 and 5 pairs of salt bridges generating -929.8±88.5 and -989.9±94.0 kcal/mol of non-covalent binding energy, respectively. Our molecular dynamic simulation showing lower probability of salt bridge formation with less non-covalent binding energy between VWF binding with the biologically loss of function G233D mutant of GPIbα as compared to wild-type, equal function, and gain of function mutant suggest that biological functions of macromolecules such as GPIbα are influenced by their small changes in physical characteristics.

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“…2). A practical example of this is the Chemistry at Harvard Macromolecular Mechanics (CHARMM) HPC project that uses quantum mechanics and Newton's 2 nd law to calculate muscle contraction by myosin-actin interactions 14) , protein structure change caused by a point mutation in patients with pulmonary artery hypertension 15) , prediction of the mechanism of platelet-type von Willebrand disease 16,17) , and so on. These successes indicate that HPC enables the modeling of complex biological phenomena that influence CV events from very simple equations, may help understanding them at the theoretical level, and may even identify a new therapeutic target by resolving the dynamic protein structure mediating biological functions.…”

Section: Advance Publication Journal Of Atherosclerosis and Thrombosismentioning

confidence: 99%

The Future Role of High-Performance Computing in Cardiovascular Medicine and Science -Impact of Multi-Dimensional Data Analysis-

Goto

McGuire

2022

JAT

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Advances in High-performance computing (HPC) technology have reached the capacity to inform cardiovascular (CV) science in the realm of both inductive and constructive approaches. Clinical trials allow for the comparison of the effect of an intervention without the need to understand the mechanism. This is a typical example of an inductive approach. In the HPC field, training an artificial intelligence (AI) model, constructed by neural networks, to predict future CV events with the use of large scale multi-dimensional datasets is the counterpart that may rely on as well as inform understanding of mechanistic underpinnings for optimization. However, in contrast to clinical trials, AI can calculate event risk at the individual level and has the potential to inform and refine the application of personalized medicine.Despite this clear strength, results from AI analyses may identify otherwise unidentified/unexpected (i.e. non-intuitive) relationships between multi-dimensional data and clinical outcomes that may further unravel potential mechanistic pathways and identify potential therapeutic targets, therebycontributing to the parsing of observational associations from causal links. The constructive approach will remain critical to overcome limitations of existing knowledge and anchored biases to actualize a more sophisticated understanding of the complex pathobiology of CV diseases.HPC technology has the potential to underpin this constructive approach in CV basic and clinical science. In general, even complex biological phenomena can be reduced to combinations of simple biological/chemical/ physical laws. In the deductive approach, the focus/intent is to explain complex CV diseases by combinations of simple principles.

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Prediction of binding characteristics between von Willebrand factor and platelet glycoprotein Ibα with various mutations by molecular dynamic simulation

Cited by 10 publications

References 47 publications

Omega-3 fatty acid epoxides produced by PAF-AH2 in mast cells regulate pulmonary vascular remodeling

Omega-3 fatty acid epoxides produced by PAF-AH2 in mast cells regulate pulmonary vascular remodeling

Physical Characteristics of von Willebrand Factor Binding with Platelet Glycoprotein Ibɑ Mutants at Residue 233 Causing Various Biological Functions

The Future Role of High-Performance Computing in Cardiovascular Medicine and Science -Impact of Multi-Dimensional Data Analysis-

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