Natural variants of von Willebrand factor R1205 causing von Willebrand disease with accelerated von Willebrand factor clearance: In silico docking models and energetics of the interaction with both LRP1 and GpIb A1 domain

Type 1 von Willebrand disease (VWD) is often caused by variants in von Willebrand factor (VWF), including p.R1205H ("Vicenza mutation"), which accelerate VWF clearance via macrophage receptor LRP1 and impair platelet adhesion and activation. However, the structural mechanisms underlying these phenotypes remain partially unclear. Here, we use integrative computational modeling (I-TASSER, HADDOCK2.4, and PRODIGY) to predict how p.R1205H/C/L/S variants alter VWF interaction with LRP1 and its platelet receptor GPIb alpha that binds to the A1 VWF domain. Our models reveal that R1205 acts as a structural hinge: its variants disrupt polar networks in VWF's D3 domain, exposing neo-epitopes that enhance LRP1 binding (Delta Delta G up to -5.3 kcal/mol) while destabilizing the A1 domain's alpha 1-beta 2 loop, reducing GPIb alpha affinity (congruent to 30-fold for R1205L/C). These findings explain clinical observations, p.R1205H rapid clearance yet retained platelet adhesion, and establish R1205 as a dual-functional switch regulating VWF circulatory lifetime and hemostatic activity. This analytical procedure provides a template for predicting pathogenicity of VWF variants and designing targeted therapies for VWD.