Browse
Submit Data
Databases
API
Help

Dataset Information

51 Views

0 Connections

0 Citations

0 Reanalyses

0 Downloads

Omics score: 0

Probing the Twisted Structure of Sickle Hemoglobin Fibers via Particle Simulations.

ABSTRACT: Polymerization of sickle hemoglobin (HbS) is the primary pathogenic event of sickle cell disease. For insight into the nature of the HbS polymer fiber formation, we develop a particle model-resembling a coarse-grained molecular model-constructed to match the intermolecular contacts between HbS molecules. We demonstrate that the particle model predicts the formation of HbS polymer fibers by attachment of monomers to rough fiber ends and the growth rate increases linearly with HbS concentration. We show that the characteristic 14-molecule fiber cross section is preserved during growth. We also correlate the asymmetry of the contact sites on the HbS molecular surface with the structure of the polymer fiber composed of seven helically twisted double strands. Finally, we show that the same asymmetry mediates the mechanical and structural properties of the HbS polymer fiber.

SUBMITTER: Lu L

PROVIDER: S-EPMC4940994 | biostudies-literature | 2016 May

REPOSITORIES: biostudies-literature

ACCESS DATA

Json Xml

Publications

Probing the Twisted Structure of Sickle Hemoglobin Fibers via Particle Simulations.

Lu Lu L Li Xuejin X Vekilov Peter G PG Karniadakis George Em GE

Biophysical journal 20160501 9

Polymerization of sickle hemoglobin (HbS) is the primary pathogenic event of sickle cell disease. For insight into the nature of the HbS polymer fiber formation, we develop a particle model-resembling a coarse-grained molecular model-constructed to match the intermolecular contacts between HbS molecules. We demonstrate that the particle model predicts the formation of HbS polymer fibers by attachment of monomers to rough fiber ends and the growth rate increases linearly with HbS concentration. W ...[more]

PMID: 27166816

Similar Datasets

Probing vasoocclusion phenomena in sickle cell anemia via mesoscopic simulations.

Project description:Vasoocclusion crisis is a key hallmark of sickle cell anemia. Although early studies suggest that this crisis is caused by blockage of a single elongated cell, recent experiments have revealed that vasoocclusion is a complex process triggered by adhesive interactions among different cell groups in multiple stages. However, the quantification of the biophysical characteristics of sickle cell anemia remains an open issue. Based on dissipative particle dynamics, we develop a multiscale model for the sickle red blood cells (SS-RBCs), accounting for diversity in both shapes and cell rigidities, to investigate the precise mechanism of vasoocclusion. First, we investigate the adhesive dynamics of a single SS-RBC in shear flow and static conditions, and find that the different cell groups (SS2: young-deformable SS-RBCs, ISCs: rigid-irreversible SS-RBCs) exhibit heterogeneous adhesive behavior due to the diverse cell morphologies and membrane rigidities. We quantify the observed adhesion behavior (in static conditions) in terms of a balance of free energies due to cell adhesion and deformation, and propose a power law that relates the free-energy increase as a function of the contact area. We further simulate postcapillary flow of SS-RBC suspensions with different cell fractions. The more adhesive SS2 cells interact with the vascular endothelium and trap ISC cells, resulting in vasoocclusion in vessels less than 12-14 μm depending on the hematocrit. Under inflammation, adherent leukocytes may also trap ISC cells, resulting in vasoocclusion in even larger vessels.

| S-EPMC3710812 | biostudies-literature

Crystal structure of carbonmonoxy sickle hemoglobin in R-state conformation.

Project description:The fundamental pathophysiology of sickle cell disease is predicated by the polymerization of deoxygenated (T-state) sickle hemoglobin (Hb S) into fibers that distort red blood cells into the characteristic sickle shape. The crystal structure of deoxygenated Hb S (DeoxyHb S) and other studies suggest that the polymer is initiated by a primary interaction between the mutation βVal6 from one Hb S molecule, and a hydrophobic acceptor pocket formed by the residues βAla70, βPhe85 and βLeu88 of an adjacent located Hb S molecule. On the contrary, oxygenated or liganded Hb S does not polymerize or incorporate in the polymer. In this paper we present the crystal structure of carbonmonoxy-ligated sickle Hb (COHb S) in the quaternary classical R-state at 1.76Å. The overall structure and the pathological donor and acceptor environments of COHb S are similar to those of the isomorphous CO-ligated R-state normal Hb (COHb A), but differ significantly from DeoxyHb S as expected. More importantly, the packing of COHb S molecules does not show the typical pathological interaction between βVal6 and the βAla70, βPhe85 and βLeu88 hydrophobic acceptor pocket observed in DeoxyHb S crystal. The structural analysis of COHb S, COHb A and DeoxyHb S provides atomic level insight into why liganded hemoglobin does not form a polymer.

| S-EPMC4859812 | biostudies-literature

Topological band structure via twisted photons in a degenerate cavity.

Project description:Synthetic dimensions based on particles' internal degrees of freedom, such as frequency, spatial modes and arrival time, have attracted significant attention. They offer ideal large-scale lattices to simulate nontrivial topological phenomena. Exploring more synthetic dimensions is one of the paths toward higher dimensional physics. In this work, we design and experimentally control the coupling among synthetic dimensions consisting of the intrinsic photonic orbital angular momentum and spin angular momentum degrees of freedom in a degenerate optical resonant cavity, which generates a periodically driven spin-orbital coupling system. We directly characterize the system's properties, including the density of states, energy band structures and topological windings, through the transmission intensity measurements. Our work demonstrates a mechanism for exploring the spatial modes of twisted photons as the synthetic dimension, which paves the way to design rich topological physics in a highly compact platform.

| S-EPMC9018724 | biostudies-literature

Cholesterol-Modified MIR29B Induces Fetal Hemoglobin via targeting DNMT3A in Townes Sickle Cell Mice

Project description:MicroRNA (miRNA) molecules hold promise as potential therapeutics capable of silencing target gene expression through RNA interference. The delivery of miRNAs without degradation has posed a significant challenge to their clinical use. However, cholesterol-conjugated miRNA has emerged as a promising delivery approach thanks to its low toxicity and high efficiency. We previously showed that MIR29B by 28-day continuous infusion using subcutaneous mini osmotic pump delivery, MIR29B induces HbF. The present study delves into evaluating intermittent delivery of a cholesterol-conjugate of MIR29B (Chol-MIR29B), to induce fetal hemoglobin (HbF) in Townes sickle cell mice. Therefore, we conducted additional in vivo studies to test intermittent dosing of Chol-MIR29B in Townes sickle cell mice. Blood was processed for complete blood count with differential and reticulocytes at weeks 0, 2, and 4, and γ-globin gene reactivation was determined by RT-qPCR. The percentage of HbF-positive cells was measured by flow cytometry. RNA seq was performed on the peripheral blood of mice treated with MIR29B. Mice treated with Chol-MIR29B exhibited normal behavior and weight gain. While there was no direct effect of Chol-MIR29B on γ-globin reactivation, delivery of Chol-MIR29B after 4 weeks of treatment significantly increased the percentage of HbF positive cells by up to 15-fold. Additionally, there were no toxic effects on complete blood counts and differential or activation of oncogenes as determined by RNA seq, supporting the safety of Chol-MIR29B while inducing HbF expression. Our results provide the first evidence of the ability of Chol-MIR29B to induce HbF in sickle cell disease transgenic mice.

2025-06-18 | GSE276352 | GEO

Fetal hemoglobin in sickle cell anemia.

Project description:Fetal hemoglobin (HbF) is the major genetic modulator of the hematologic and clinical features of sickle cell disease, an effect mediated by its exclusion from the sickle hemoglobin polymer. Fetal hemoglobin genes are genetically regulated, and the level of HbF and its distribution among sickle erythrocytes is highly variable. Some patients with sickle cell disease have exceptionally high levels of HbF that are associated with the Senegal and Saudi-Indian haplotype of the HBB-like gene cluster; some patients with different haplotypes can have similarly high HbF. In these patients, high HbF is associated with generally milder but not asymptomatic disease. Studying these persons might provide additional insights into HbF gene regulation. HbF appears to benefit some complications of disease more than others. This might be related to the premature destruction of erythrocytes that do not contain HbF, even though the total HbF concentration is high. Recent insights into HbF regulation have spurred new efforts to induce high HbF levels in sickle cell disease beyond those achievable with the current limited repertory of HbF inducers.

| S-EPMC3139383 | biostudies-literature

Fetal hemoglobin in sickle cell anemia.

Project description:Fetal hemoglobin (HbF) can blunt the pathophysiology, temper the clinical course, and offer prospects for curative therapy of sickle cell disease. This review focuses on (1) HbF quantitative trait loci and the geography of β-globin gene haplotypes, especially those found in the Middle East; (2) how HbF might differentially impact the pathophysiology and many subphenotypes of sickle cell disease; (3) clinical implications of person-to-person variation in the distribution of HbF among HbF-containing erythrocytes; and (4) reactivation of HbF gene expression using both pharmacologic and cell-based therapeutic approaches. A confluence of detailed understanding of the molecular basis of HbF gene expression, coupled with the ability to precisely target by genomic editing most areas of the genome, is producing important preliminary therapeutic results that could provide new options for cell-based therapeutics with curative intent.

| S-EPMC7685210 | biostudies-literature

Salubrinal induces fetal hemoglobin expression via the stress-signaling pathway in human sickle erythroid progenitors and sickle cell disease mice

Project description:Sickle cell disease (SCD) is an inherited blood disorder caused by a mutation in the HBB gene leading to hemoglobin S production and polymerization under hypoxia conditions leading to vaso-occlusion, chronic hemolysis, and progressive organ damage. This disease affects ~100,000 people in the United States and millions worldwide. An effective therapy for SCD is fetal hemoglobin (HbF) induction by pharmacologic agents such as hydroxyurea, the only Food and Drug Administration-approved drug for this purpose. Therefore, the goal of our study was to determine whether salubrinal (SAL), a selective protein phosphatase 1 inhibitor, induces HbF expression through the stress-signaling pathway by activation of p-eIF2α and ATF4 trans-activation in the γ-globin gene promoter. Sickle erythroid progenitors treated with 24μM SAL increased F-cells levels 1.4-fold (p = 0.021) and produced an 80% decrease in reactive oxygen species. Western blot analysis showed SAL enhanced HbF protein by 1.6-fold (p = 0.0441), along with dose-dependent increases of p-eIF2α and ATF4 levels. Subsequent treatment of SCD mice by a single intraperitoneal injection of SAL (5mg/kg) produced peak plasma concentrations at 6 hours. Chronic treatments of SCD mice with SAL mediated a 2.3-fold increase in F-cells (p = 0.0013) and decreased sickle erythrocytes supporting in vivo HbF induction.

| S-EPMC9154101 | biostudies-literature

Mesoscale Simulations of Structure Formation in Polyacrylonitrile Nascent Fibers Induced by Binary Solvent Mixture.

Project description:Polyacrylonitrile (PAN) is widely used as a raw material for the production of high-modulus carbon fibers, the internal structure of which is directly affected by the spinning of the precursor. Although PAN fibers have been studied for a long time, the formation of their internal structure has not been sufficiently investigated theoretically. This is due to the large number of stages in the process and the parameters controlling them. In this study, we present a mesoscale model describing the evolution of nascent PAN fibers during the coagulation. It is constructed within the framework of a mesoscale dynamic density functional theory. We use the model to study the influence of a combined solvent of dimethyl sulfoxide (DMSO, a good solvent) and water (a non-solvent) on the microstructure of the fibers. A porous structure of PAN is formed as a result of the microphase separation of the polymer and the residual combined solvent at a high water content in the system. The model shows that one of the possible ways to obtain the homogeneous fiber structure is to slow down the coagulation by increasing the amount of good solvent in the system. This result is in agreement with the existing experimental data and confirms the efficiency of the presented model.

| S-EPMC10253059 | biostudies-literature

Two types of morphologically distinct fibers comprising Gallionella ferruginea twisted stalks.

Project description:Two morphologically distinct extracellular stalk fibers produced by Gallionella ferruginea were compared by electron microscopy and elemental analysis. The thick- and fine-fiber stalks were different in structure on a micrometer scale and in the site on the mother cell to which they were attached, but on a nanometer scale they were similar in ultrastructure and in the elemental composition of their basic fiber matrix.

| S-EPMC4036057 | biostudies-literature

Interrogating RNA-Small Molecule Interactions with Structure Probing and Artificial Intelligence-Augmented Molecular Simulations.

Project description:While there is increasing interest in the study of RNA as a therapeutic target, efforts to understand RNA-ligand recognition at the molecular level lag far behind our understanding of protein-ligand recognition. This problem is complicated due to the more than 10 orders of magnitude in time scales involved in RNA dynamics and ligand binding events, making it not straightforward to design experiments or simulations. Here, we make use of artificial intelligence (AI)-augmented molecular dynamics simulations to directly observe ligand dissociation for cognate and synthetic ligands from a riboswitch system. The site-specific flexibility profiles from our simulations are compared with in vitro measurements of flexibility using selective 2' hydroxyl acylation analyzed by primer extension and mutational profiling (SHAPE-MaP). Our simulations reproduce known relative binding affinity profiles for the cognate and synthetic ligands, and pinpoint how both ligands make use of different aspects of riboswitch flexibility. On the basis of our dissociation trajectories, we also make and validate predictions of pairs of mutations for both the ligand systems that would show differing binding affinities. These mutations are distal to the binding site and could not have been predicted solely on the basis of structure. The methodology demonstrated here shows how molecular dynamics simulations with all-atom force-fields have now come of age in making predictions that complement existing experimental techniques and illuminate aspects of systems otherwise not trivial to understand.

| S-EPMC9228567 | biostudies-literature

OmicsDI is part of the ELIXIR infrastructure

OmicsDI is an Elixir interoperability service. Learn more ›

Tweets

OmicsDI Databases

PRIDE
PeptideAtlas
MassIVE
JPOST Repository
Physiome Model Repository

EGA
EVA
ENA
LINCS
PAXDB
Cell Collective

MetaboLights
Metabolomics Workbench
MetabolomeExpress
GNPS
BioModels
FAIRDOMHub

ArrayExpress
dbGaP
ExpressionAtlas
GEO
NODE

Information

Databases
Help
API
Contact us
Code on GitHub
Terms of use
Submit Data