Genesis v8: A C-alpha-only Geometric Framework for Protein-Level Allosteric Propensity Classification

Genesis v8 presents a lightweight, interpretable framework for protein-level allosteric propensity classification using five C-alpha-only geometric descriptors: Fiedler eigenvalue (lambda2), Lo-Shu lattice transfer energy (LTE), convex-hull concavity score (CHC), backbone rigidity fraction (fracᵣigid), and pocket-region flexibility (pocketflex). Four-tier validation: Internal CV (n=768): standard AUC=0. 898 0. 871, 0. 921; homology-aware AUC=0. 701 External positive — AlloBench blind test (n=430): Sensitivity=80. 2% @0. 50, 88. 8% @0. 30 Specificity pilot (n=220, exploratory lower bound): AUC=0. 76, BalAcc=0. 71 @0. 80 Mechanistic spatial (Route 2, n=101): hinge-to-site 11. 7 A vs 15 A random; p=0. 0022 Proteome feasibility: 20, 158 human AlphaFold2 structures screened in <3 h on CPU. No GPU required. v8 is the first Genesis version with fully separated four-tier validation and honest negative-set contamination analysis. Previous versions: v2 (10. 5281/zenodo. 20187149), v3 ESM2 Route-A (10. 5281/zenodo. 20202158). Route 2 companion: 10. 5281/zenodo. 20251581.