Proteins in a shear flow

Szymczak, Piotr; Cieplak, Marek

doi:10.1063/1.2795725

Cited by 54 publications

(83 citation statements)

References 54 publications

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“…91,92 They noted that the hydrodynamic drag on a grafted protein chain in extensional flow increases along the chain length as the polymer unfolds. Therefore, the initiation of unfolding triggers a positive feedback mechanism which leads to the rapid unraveling of the entire chain to the exclusion of intermediate states.…”

Section: Molecular Models and Theoretical Aspectsmentioning

confidence: 99%

The effects of shear flow on protein structure and function

Bekard

Asimakis

Bertolini³

et al. 2011

Biopolymers

180

140

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Toxoplasma gondii usually causes an asymptomatic and then latent infection in human adults; however, a potentially fatal disseminated form can occur in immunocompromised patients. Given that the diagnosis of acute Toxoplasma infection, as opposed to latent disease, relies on finding direct evidence of T. gondii infection in tissue, pathologic examination is critical. There have only been a few reports describing the cytomorphology of Toxoplasma in exfoliative cytology, and no reports of the findings in Thin Prep. In this report, we describe a fatal case of toxoplasmosis in a cardiac transplant patient that was diagnosed by respiratory cytopathology. Although the extracellular organisms were well visualized on the Wright‐Giemsa stained cytospin, they were only faintly seen on the Pap‐stained cytospin trapped within mucin and were not easily appreciated on the ThinPrep slides nor the H&E stained cell block sections. An immunohistochemical stain for Toxoplasma performed on the cell block was strongly positive, and an autopsy performed on the patient confirmed disseminated infection. Our case illustrates that the diagnosis of Toxoplasma in exfoliative cytology specimens can be challenging since organisms are not well visualized on ThinPrep or Pap‐stained material; therefore, Wright‐Giemsa stained material can be particularly helpful. Diagn. Cytopathol. 2012. © 2011 Wiley Periodicals, Inc.

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Section: Molecular Models and Theoretical Aspectsmentioning

confidence: 99%

The effects of shear flow on protein structure and function

Bekard

Asimakis

Bertolini³

et al. 2011

Biopolymers

180

140

View full text Add to dashboard Cite

show abstract

“…These data accord with experimental and theoretical investigations using proteins, DNA, organic polymers, and coarse-grained models which suggest that flow applies a stretching force to molecules along the flow field that is proportional to the strain rate. As the hydrodynamic drag of the protein increases as it unfolds, the already destabilized protein has a greater susceptibility to unfold further and interact with other proteins (40)(41)(42)(43)(44), which increases its size.…”

Section: Design and Computational Characterization Of Extensional Flowmentioning

confidence: 99%

Inducing protein aggregation by extensional flow

Dobson

Kumar

Willis

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

129

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Relative to other extrinsic factors, the effects of hydrodynamic flow fields on protein stability and conformation remain poorly understood. Flow-induced protein remodeling and/or aggregation is observed both in Nature and during the large-scale industrial manufacture of proteins. Despite its ubiquity, the relationships between the type and magnitude of hydrodynamic flow, a protein's structure and stability, and the resultant aggregation propensity are unclear. Here, we assess the effects of a defined and quantified flow field dominated by extensional flow on the aggregation of BSA, β 2 -microglobulin (β 2 m), granulocyte colony stimulating factor (G-CSF), and three monoclonal antibodies (mAbs). We show that the device induces protein aggregation after exposure to an extensional flow field for 0.36-1.8 ms, at concentrations as low as 0.5 mg mL −1 . In addition, we reveal that the extent of aggregation depends on the applied strain rate and the concentration, structural scaffold, and sequence of the protein. Finally we demonstrate the in situ labeling of a buried cysteine residue in BSA during extensional stress. Together, these data indicate that an extensional flow readily unfolds thermodynamically and kinetically stable proteins, exposing previously sequestered sequences whose aggregation propensity determines the probability and extent of aggregation.extensional flow | aggregation | unfolding | bioprocessing | antibody P roteins are dynamic and metastable and consequently have conformations that are highly sensitive to the environment (1). Over the last 50 y the effect of changes in temperature, pH, and the concentration of kosmatropic/chaotropic agents on the conformational energy landscape of proteins has become well understood (1). This, in turn, has allowed a link to be established between the partial or full unfolding of proteins and their propensity to aggregate (2). The force applied onto a protein as a consequence of hydrodynamic flow has also been observed to trigger protein aggregation and has fundamental (3), medical (4), and industrial relevance, especially in the manufacture of biopharmaceuticals (5-8). Although a wealth of studies have been performed (7,(9)(10)(11)(12)(13), no consensus has emerged on the ability of hydrodynamic flow to induce protein aggregation (7,14,15). This is due to the wide variety of proteins used (ranging from lysozyme, BSA, and alcohol dehydrogenase to IgGs), differences in the type of flow field generated (e.g., shear, extensional, or mixtures of these), and to the presence or absence of an interface (16). A shearing flow field (Fig. 1A, Top) is caused by a gradient in velocity perpendicular to the direction of travel and is characterized by the shear rate (s −1 ). This results in a weak rotating motion of a protein alongside translation in the direction of the flow. An extensional flow field (Fig. 1A, Bottom) is generated by a gradient in velocity in the direction of travel and is characterized by the strain rate (s −1 ). A protein in this type of flow would experien...

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“…The structure of this ansatz, which effectively factorizes D into individual two-body contributions, is taken from equation (14). The scaling factor C i takes care that for each individual coordinate its unperturbed diffusion coefficient D ii is regained 9 , while β ij allows for different weights when √ D is used instead of D in equation (15).…”

Section: The Truncated Expansion Ansatzmentioning

confidence: 99%

“…As the already approximated direct interactions are most important for the dynamics of most biologically interesting association and dissociation processes, the time consuming HI is often neglected 11 . For applications to polymers or the dynamics of DNA, however, it may be important to explicitly include HI in order to reproduce the correct dynamic behavior 12,13,14 .…”

Section: Introductionmentioning

confidence: 99%

An O(N2) approximation for hydrodynamic interactions in Brownian dynamics simulations

Geyer

Winter²

2009

The Journal of Chemical Physics

102

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In the Ermak-McCammon algorithm for Brownian Dynamics, the hydrodynamic interactions (HI) between N spherical particles are described by a 3N ×3N diffusion tensor. This tensor has to be factorized at each timestep with a runtime of O(N 3 ), making the calculation of the correlated random displacements the bottleneck for many-particle simulations. Here we present a faster algorithm for this step, which is based on a truncated expansion of the hydrodynamic multi-particle correlations as two-body contributions. The comparison to the exact algorithm and to the Chebyshev approximation of Fixman verifies that for bead-spring polymers this approximation yields about 95% of the hydrodynamic correlations at an improved runtime scaling of O(N 2 ) and a reduced memory footprint. The approximation is independent of the actual form of the hydrodynamic tensor and can be applied to arbitrary particle configurations. This now allows to include HI into large manyparticle Brownian dynamics simulations, where until now the runtime scaling of the correlated random motion was prohibitive.

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Proteins in a shear flow

Cited by 54 publications

References 54 publications

The effects of shear flow on protein structure and function

The effects of shear flow on protein structure and function

Inducing protein aggregation by extensional flow

An O(N2) approximation for hydrodynamic interactions in Brownian dynamics simulations

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