Mapping the Peptide Interaction Fingerprint of the Behcet's disease associated HLA-B*51

Abstract

The strongest genetic risk factor for Behcets disease, a relapsing inflammatory disorder marked by recurrent mucocutaneous ulcers and uveitis, is an allele of the class I major histocompatibility complex (MHC-I) molecule, which presents intracellular peptides to CD8+ T cells. The molecular mechanisms linking the peptide preferences of this allele (HLA-B*51:01) to dysregulated immunity remain unclear, limiting efforts to design peptide-based modulators of antigen presentation. Here, we define HLA-B*51:01s peptide selection rules by mapping the "interaction fingerprint" of 36 self-peptides using long-duration all-atom MD simulations. These uncovered a conserved hydrophobic-polar blueprint that is tuned by peptide length. High-speed atomic force microscopy rate in silico pulling experiments suggest a three-tier hierarchy of mechanical resilience: 9-mers resist the highest forces, 8-mers exhibit intermediate resistance, and 10/11-mers rupture most easily. Our comprehensive analysis provides an atomistic framework for understanding the molecular mechanisms underlying HLA-B*51:01 pathobiology and offers quantitative parameters to guide the design of therapeutic peptides or small molecules to modulate antigen presentation in Behcets disease. STATEMENT OF SIGNIFICANCEBehcets disease is strongly linked to HLA-B*51:01, a molecule that displays protein fragments to killer T cells, yet how this allele selects its peptides is poorly understood. Here, we combine all-atom equilibrium molecular dynamics simulations with steered MD pulling simulations that mimic high-speed atomic force microscopy experiments to map how 36 self-peptides of different lengths engage the HLA-B*51:01 groove. We uncover a conserved hydrophobic-polar interaction blueprint and show that 9-mers form the mechanically most resilient complexes, whereas shorter or longer peptides detach more easily under force. This length-tuned interaction "fingerprint" provides an atomistic framework for understanding HLA-B*51:01-driven immune dysregulation and guides the rational design of peptide-based or small-molecule modulators for Behcets disease.