Details of the model of WT VWF and heterozygous in cis p.R924Q/p.A2178S (sequence Ser764-Val2191) obtained with the I-Tasser program. (A) Hydrogen bonds between the side chain of R924 with the side chains of surrounding residues in WT form. These bonds are completely lost in the heterozygous in cis mutant. The figure, prepared with the PyMol software, shows the polar interactions (dashed lines in yellow) of the side chain of Arg924 with surrounding amino acids. Structure of the α4 chain of the D4 domain (H2169-A2181 in the red cartoon with the side chain of A2178 in yellow sticks) of the WT VWF form (B) and in the heterozygous in cis p.R924Q/p.A2178S mutant (H2169-A2181 in the red cartoon with the side chain of S2178 in yellow sticks) (C). To assess the putative structural effect of the in cis heterozygous p.R924Q/p.A2178S mutations over the entire region from Ser764 to Val2191, also comprising part of the D4 domain (V1875-V2191),⁵  we modeled this region on the I-TASSER threading modeling server (Iterative Threading ASSEmbly Refinement; http://zhanglab.ccmb.med.umich.edu/I-TASSER/).^25,26