Multivalent binding mechanism of LRP1-fibrinogen interactions revealed by QCM-D and molecular dynamics

Inflammatory diseases involve dysregulated coagulation and impaired clearance pathways, leading to altered behavior of plasma proteins and their receptors. Fibrinogen, a key acute-phase protein, is elevated in systemic inflammation, yet its clearance mechanisms remain poorly understood. We previously identified a stable, sialylation-dependent interaction between low-density lipoprotein receptor-related protein 1 (LRP1) and fibrinogen, suggesting a potential role for LRP1 in fibrinogen homeostasis. Here, we quantitatively and structurally define this interaction using an integrated biophysical and computational approach. A modified quartz crystal microbalance assay revealed a moderately strong and specific affinity (K_d ≈ 10² nM) between LRP1 and fibrinogen. Molecular dynamics simulations uncovered a previously unrecognized multimodal binding mechanism, wherein LRP1 engages four distinct fibrinogen sites through heterogeneous electrostatic, hydrophobic, and cation-π interactions. This multivalent interface (∼3167 Ų) extends canonical LRP1-ligand recognition patterns and provides a mechanistic basis for fibrinogen clearance under inflammatory conditions. Our findings advance the structural understanding of LRP1 as a clearance receptor and establish a framework for targeting LRP1-fibrinogen interactions in thromboinflammatory disease.