Abstract
<title>Abstract</title> <p>Polymorphism at position 156 of HLA-B*35 modulates T-cell receptor (TCR) triggering through dynamic entropy control rather than static binding affinity. While HLA-B*3501 (Leu156) and HLA-B*3508 (Arg156) present the 13-mer Epstein-Barr virus (EBV) peptide with identical binding affinities, only B*3508 induces a cytotoxic T-lymphocyte (CTL) response (1, 2). Here, we present a segmental dynamics framework showing how the positively charged Arg156 residue coordinates a structured, water-mediated electrostatic network beneath the peptide-binding groove. Normalized crystallographic B-factor analysis reveals that this interstitial water scaffold drastically suppresses thermal motion across the central peptide bulge (residues P3–P6). Electrostatic potential calculations show that Arg156 neutralizes local negative charges at Asp114, pinning the peptide hinge points and pre-organizing the central recognition loop. By dampening conformational flexibility, the Arg156-driven solvent network lowers the entropic penalty for TCR engagement, permitting kinetic proofreading and signaling (5–9). These findings establish interstitial water networks as active mechanical rheostats in antigen recognition with direct implications for rational immunogen design.</p>