Lo-Shu/Markov-Fiedler Framework v4: Full Size-Controlled Allosteric Benchmark (n=569), Multi-Target Vina Discrepancy (n=46), and Honest Positioning

Full validation of the Lo-Shu/Markov-Fiedler C-alpha geometric framework across three tasks. (1) Allosteric classification on n=569 proteins (486 allosteric from UniProt KW-0021+ASBench, 83 orthosteric-only). Size confound (rho (CHC, n) =0. 860) confirmed and corrected via OLS residualization. After correction: CHC loses significance; lambda₂ᵣes (p=0. 04), flexᵣes (p=0. 003), rigᵣes (p=0. 001) retained. RF AUC=0. 882 (permutation p=0. 005). (2) Multi-target Vina discrepancy: 8 targets, 46 ligands, 37/46 under-scored; domain-boundary hypothesis supported for kinases, not HIV-PR (honest negative). (3) Calibrated claim: original lightweight integration, not world-first. Next step: run PASSer/ALLO on same dataset for direct head-to-head comparison.