From selenium to sulfur: predictive modeling unveils conformational and bonding changes in selenoproteins

Selenoproteins, defined by the incorporation of the 21st amino acid - selenocysteine (Sec) - orchestrate essential redox, endocrine, and metabolic pathways in humans, yet high‑resolution structures exist for only a minority of the 25 family members. Leveraging the AlphaFold 3 (AF3), we generated full‑length atomic models for all human selenoproteins together with in‑silico Sec-to-Cys variants. AF3 achieved high confidence for 22 proteins and sub‑Å agreement with the one experimentally solved glutathione peroxidase 4 (GPX4). Global comparison of native and mutant models revealed that Sec-to-Cys substitution preserves overall fold in nineteen proteins but locally disrupts or re‑wires intramolecular selenenyl‑sulfide linkages in six cases. Structure‑based clustering uncovered a conserved "Se‑thioredoxin‑like" core in fifteen selenoproteins. AF3 additionally predicted potential GPX4 homodimeric assemblies, consistent with the dimeric forms observed in native gels from brain tissue and cell lines. Together, these AF3 models constitute the comprehensive structural atlas of the human selenoproteome, elucidate the fold‑specific positioning of Sec. The dataset provides a foundation for mechanistic dissection, evolutionary analyses, and rational drug design targeting selenium‑dependent redox biology.