How VWF and its domains experience force. (A-E) Force on domain termini. Domains are shown in cartoon representation, colored in rainbow from N terminus (blue) to C terminus (red). Disulfides and an Arg in A1 that participates in H bonds are shown in stick with orange sulfurs and blue nitrogens. Arrows show how tensile (elongational) force is exerted across domains when they are present in an elongated VWF concatemer experiencing hydrodynamic force. (A-C) are in similar but slightly different orientations. (A) A1 has a highly conserved set of hydrogen bonds external to the long-range disulfide (black dashes) seen in all crystal structures.^64-66,108  (B) A2 has a C-terminal, vicinal disulfide bond and a bound Ca²⁺ ion (silver sphere).^51,54,55  (C). A3, in contrast to A1, has no hydrogen bonds external to its long-range disulfide, which shows flexibility, with differences in position among structures or disorder.^77,107,109  (D) The CTCK domain is highly reinforced against elongational force.⁴⁸  (E) The VWC domain has no hydrophobic core and flexibility between its 2 subdomains.⁸  VWC domains in VWF are not yet characterized at high resolution and are known from collagen IIA⁸  and crossveinless 2.⁹  (F) Portion of a VWF concatemer at pH 7.4 in negative stain EM.¹  Arrow and arrowheads mark approximate monomer-monomer interfaces at tail-to-tail (arrow) and head-to-head (arrowhead) positions. (G-I) VWF concatemer schematics. (G) interprets the conformation captured in EM in panel F. (H) How the conformation in panel G would be straightened by elongational force. Panel I schematizes at larger scale domain architecture under elongational force.