PB0811 - Natural variants of von Willebrand factor R1205 associated with type 1 von Willebrand disease: in-silico docking models and energetics of the interactions with the macrophagic scavenger receptor LRP1.

Background: “Vicenza von Willebrand Disease” is characterized by an accelerated VWF clearance. The VWF pathological variant is characterized by the p.R1205H substitution in the D3 domain altering its regulatory role in VWF clearance, occurring also through the interaction with the macrophagic scavenger receptor LRP1. The VWF-R1205H variant half-life is markedly reduced compared to the wild-type form. The Arg1205 residue seems to play a crucial role. Other R1205 missense mutations responsible for an accelerated clearance by LRP1 are: p.R1205S; p.R1205C, and p.R1205L.

Aims: The structural consequences of the R1205-VWF pathological variants and their interaction with LRP1 were evaluated by in-silico molecular modeling methods.

Methods: The monomer WT-VWF, VWF-R1205 variants and LRP1-clusterIV predictive models were obtained by I-TASSER and FG-MD programs. The docking complexes LRP1-(ClusterIV)-VWF were investigated in-silico through the ClusPro program. The domains involved and the relative contribution of hydrogen and hydrophobic energies were analyzed by the PDBsum platform. The prediction of the binding affinity was calculated through the PRODIGY program.

Results: The His residue in the p.R1205H variant induces the lack of the hydrogen bond between Arg1205 and Asp1249 altering the surrounding region (1134-1298) and producing allosteric rearrangements. Compared to the WT, the p.R1205H model showed an increment of salt and hydrogen bonds with LRP1. The p.R1205S and p.R1205C variants cause the “widening” of the monomers, thus LRP1 bridges two regions of the VWF variants (Fig. 1). The p.R1205L variant interacts with LRP1 through Arg865-Asp952 region, not involved in the other variants. Nevertheless, the interaction surface and the binding affinity were not significantly perturbed. The PRODIGY program allowed to calculate the theoretical free energy of binding (ΔG), based on the protein-protein models by ClusPro program. Table 1 lists all the theoretical ΔG values at 37°C.

Conclusion(s): These mutations could eliminate the D’D3 domain inhibitory role on VWF clearance and create novel receptor-binding site with LRP1.