Structural and Molecular Dynamics Analysis of Human β-Defensin 1 Variants Reveals Distinct Perturbation Signatures

Human β-defensin 1 (hBD-1) is a small, disulfide-constrained antimicrobial peptide produced predominantly in the kidney and urogenital tract, where it contributes to epithelial innate defense. Genetic variation in the gene encoding hBD-1 has been associated with altered expression levels and susceptibility to infections, including infection following solid organ transplantation, yet the molecular consequences of coding substitutions in the active, mature form remain largely undefined. Here, we integrate conventional genomics, protein bioinformatics, structural modeling, and molecular dynamics to investigate the molecular consequences of 93 human-observed hBD-1 missense variants. Evaluation of hBD-1 missense variants across sequence-, structure-, and dynamics-based dimensions reveals variant-specific molecular perturbation signatures that complement conventional and static biophysical predictions. By treating naturally occurring substitutions as a perturbation series across a compact defensin scaffold, this study identifies multiple molecular routes through which sequence variation can remodel an endogenous antimicrobial peptide and prioritizes variants for direct structure-function testing. These findings provide a mechanistic framework for investigating how naturally occurring hBD-1 variation may influence peptide behavior and, ultimately, antimicrobial function.