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. However, the structural mechanisms underlying these phenotypes remain 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 GPIbα. 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 (ΔΔG up to −5.3 kcal/mol) while destabilizing the A1 domain’s α1-β2 loop, reducing GPIbα affinity (33-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 procedute provides a template for predicting pathogenicity of VWF variants and designing targeted therapies for VWD. Author Summary In our study, we explored how specific genetic changes in von Willebrand factor (VWF), a protein crucial for haemostsis, lead to a bleeding disorder called von Willebrand disease (VWD). We focused on mutations at position R1205 in VWF, known to cause rapid clearance of the protein from the bloodstream, resulting in low levels and impaired clotting. Using advanced computer modeling, we investigated how these mutations alter VWF’s interactions with two key partners: LRP1, a receptor that removes VWF from circulation, and GpIbα, a platelet receptor essential for clotting. Our models revealed that R1205 acts like a structural hinge. Mutations disrupt its stabilizing role, exposing regions that bind more tightly to LRP1, thus explaining the accelerated clearance seen in patients. Simultaneously, these changes can also weaken VWF’s ability to interact with platelets, further impairing platelet haemostatic function. This work provides a blueprint for understanding how some VWF variants cause disease and could guide the design of targeted therapies to correct or compensate for these defects, improving treatment for VWD patients.