Computational Design and Validation of a p53-SOG1 Hybrid Transcription Factor for Cancer Therapy and DNA Damage Response

Understanding cross-species DNA damage response (DDR) regulators is critical for advancing synthetic biology and cancer therapeutics. The tumor suppressor p53 (mammalian) and SOG1 (plant-specific) share functional parallels in regulating DDR, yet their hybridization remains unexplored. This study presents a novel hypothesis: a p53-SOG1 hybrid protein can retain p53’s tumor suppressive function while incorporating SOG1’s regulatory efficiency, potentially offering new avenues for cancer therapy. To test this hypothesis, we designed and computationally validated the hybrid protein using molecular docking, molecular dynamics (MD) simulations, and structural validation. Docking studies revealed enhanced DNA-binding affinity (ZDOCK score: 1453), stable structural dynamics (RMSD: 0.11 nm), and high hydration stability (SASA: 373 nm²). Hydrogen bonding (1200+ H-bonds) stabilized DNA binding. MolProbity analysis positioned the hybrid in the 100th percentile for structural accuracy. Notably, the hybrid retains p53’s tetramerization via the oligomerization (OD) and C-terminal (CTD) domains. Our findings provide strong in silico support for the feasibility of a p53-SOG1 hybrid as a functional transcription factor. Future experimental directions include expression in mammalian cells (HEK293T, HCT116), transcriptional activity assays (qPCR, luciferase reporter), and DNA-binding kinetics via Surface Plasmon Resonance (SPR). These steps will determine its viability for cancer therapeutics and cross-species synthetic biology applications.