Internal Tensile Force and A2 Domain Unfolding of von Willebrand Factor Multimers in Shear Flow
| Autor: | Alparslan Oztekin, Chuqiao Dong, Xuanhong Cheng, Michael Morabito, Wei Wei, Edmund B. Webb, X. Frank Zhang |
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| Rok vydání: | 2018 |
| Předmět: |
Models
Molecular 0301 basic medicine Biophysics ADAMTS13 Protein 01 natural sciences 03 medical and health sciences Molecular dynamics 0302 clinical medicine Protein Domains Tensile Strength von Willebrand Factor 0103 physical sciences Protein Structure Quaternary Brownian motion Protein Unfolding 030304 developmental biology Physics 0303 health sciences 010304 chemical physics Dynamics (mechanics) Proteins ADAMTS13 Biomechanical Phenomena Shear rate 030104 developmental biology Spring (device) Domain (ring theory) Protein Multimerization Shear Strength Shear flow 030217 neurology & neurosurgery |
| DOI: | 10.1101/312405 |
| Popis: | Using Brownian molecular dynamics simulations, we examine the internal dynamics and biomechanical response of von Willebrand Factor (vWF) multimers subject to shear flow. The coarse grain multimer description employed here is based on a monomer model in which the A2 domain of vWF is explicitly represented by a non-linear elastic spring whose mechanical response was fit to experimental force/extension data from vWF monomers. This permits examination of the dynamic behavior of hydrodynamic forces acting on A2 domains as a function of shear rate and multimer length, as well as position of an A2 domain along the multimer contour. Force/position data reveal that collapsed multimers exhibit a force distribution with two peaks, one near each end of the chain; unraveled multimers, however, show a single peak in A2 domain force near the center of multimers. Guided further by experimental data, significant excursions of force acting on a domain are associated with an increasing probability for A2 domain unfolding. Our results suggest that the threshold shear rate required to induce A2 domain unfolding is inversely proportional to multimer length. By examining data for the duration and location of significant force excursions, convincing evidence is advanced that unfolding of A2 domains, and therefore scission of vWF multimers by the size-regulating blood enzyme ADAMTS13, happen preferentially near the center of unraveled multimers. |
| Databáze: | OpenAIRE |
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