The von Willebrand Factor (vWF) is a large multimeric protein that aids in blood clotting. Hydrodynamic forces trigger conformational changes of vWF that regulate its binding to clotting agents in the blood. A coarse grain molecular model is proposed for the vWF multimer that incorporates observed mechanical properties of vWF monomers. Each monomer is represented by a finitely extensible nonlinear elastic (FENE) spring connecting two beads. The FENE spring represents the A2 domain in the central region of vWF monomers and it permits extensive elongation to mimic domain unfolding. The beads at each end of the FENE spring represent relatively rigid domains adjacent to A2 in vWF monomers. The spring constant and maximum extended length of the FENE spring are optimized to reproduce force-extension experimental data for the A2 domain in vWF monomers. Multimers in the model are formed by connecting beads on adjacent monomers via a stiff harmonic spring. The bead-bead interaction parameters are optimized to reproduce observed packing of vWF globules in poor solvent at zero flow experimental conditions. Brownian dynamics simulations using this model are performed to understand vWF multimer response to shear flow in both free-draining (FD) and hydrodynamic interactions (HI) cases. Results from the new model are in excellent agreement with available experimental data as well as previous coarse grain modeling predictions for vWF response to shear flow. Unique to this work, the conformation of the model A2 domains (i.e. the FENE springs) are examined in response to flow. For dimensionless Wiessenberg number Wi < 10, model A2 domains are fully coiled and this shows no dependence on the number of monomers in the molecule N. For Wi > 10, the model A2 domain size increases with increasing shear rate and this effect is greater for smaller N. This N dependence is opposite to what is observed for the conformation of the vWF multimer, where the increase in molecular extension with shear rate is more pronounced for larger N. The inverse N dependence for model A2 domain response to increasing flow is due to greater overall molecular alignment with the flow direction for larger N; increased molecular alignment manifests forces that cause less intra-monomer elongation. Fluctuations in model A2 domains were shown to increase significantly at high flow, including periodic complete extension of the domain. (C) 2015 Elsevier B.V. All rights reserved.