Universal physical principles govern the deterministic genesis of protein structure

The origin of functional proteins remains a fundamental biological enigma. Although Anfinsen’s dogma established sequence as the determinant of structure, and deep learning models can predict structures with high fidelity, the physical principles governing protein genesis itself, from prebiotic condensation to functional protein emergence, remain unresolved. This gap leaves a critical disconnect between mechanistic biological insights and artificial intelligence. Herein, we introduce a unified methodological framework ProtGenesis that recasts genesis of protein as a structured, deterministic navigation within a discrete structural space. We identify three universal principles governing this hierarchical organization: the Assembly Principle directs amino acids condensation into multilayer fractal-like architectures; the Emergence Principle ensures nascent peptides’ emergence follow deterministic spatial trajectories; and the Phase-Transition Principle describes wherein incremental residue accrual or mutations drives precise topological phase shifts from short-range to long-range order. By quantifying these trajectories with novel tripartite spatial metrics, we reveal that protein genesis is not an abstract continuum but a principle-governed physical process with measurable coordinates. ProtGenesis thus provides an universal interpretable mathematical foundation for decoding “black-box” of deep learning models and establishes a rigorous basis for exploring, understanding, and engineering the molecular blueprint of life. Graphical Abstract