Internal Tensile Force and A2 Domain Unfolding of von Willebrand Factor Multimers in Shear Flow

• Published in: Biophysical journal Vol. 115; no. 10; pp. 1860 - 1871
• Main Authors: Morabito, Michael, Dong, Chuqiao, Wei, Wei, Cheng, Xuanhong, Zhang, Xiaohui F., Oztekin, Alparslan, Webb, Edmund
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 20.11.2018; The Biophysical Society
• Subjects: ADAMTS13 Protein - metabolism; Biomechanical Phenomena; Models, Molecular; Protein Domains; Protein Multimerization; Protein Structure, Quaternary; Protein Unfolding; Proteins; Shear Strength; Tensile Strength; von Willebrand Factor - chemistry; von Willebrand Factor - metabolism
• ISSN: 0006-3495; 1542-0086; 1542-0086
• DOI: 10.1016/j.bpj.2018.09.001

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 nonlinear 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.