Fig. 1: Structural and nonstructural properties of the FVIII protein.

a To assemble the dataset we combined structural properties from the FVIII protein structure, from a multiple sequence alignment (i.e., the conservation of residues), and from a residue interaction network (RIN). In a RIN, each amino acid is a node, and two nodes are connected if the two residues are at close proximity in the structure (i.e., if their main- or side-chains are less than ~5 Å from each other). The FVIII RIN had 1336 nodes and 4074 edges. b Distribution of values of the variables related to the HA severity. Depicted is the solvent-accessible (areaSAS) and the solvent-excluded (areaSES) surface areas, the conservation of the FVIII residues (conservation score—smaller values indicate higher conservation). The degree is the number of connections that a node has, and Burt’s constraint²¹ quantifies the strategic location of a node between groups that would not be connected otherwise. The boxplots depict the median (centerline), the first and third quartiles (lower- and upper-bounds), and 1.5 times the inter-quartile range (lower- and upper whiskers). Each dot in the plot is an amino acid mutation (i.e., a clinical case report). Statistics: one-way ANOVA followed by Tukey’s post hoc test. In all cases, we used n = 171 (mild), n = 70 (moderate), and n = 123 (Severe). *** indicate Tukey’s post hoc p values < 0.001; **p value < 0.01; *p value < 0.05.