GTWY-PHB2 Engagement as a Convergence Point for Mitophagy, Iron Buffering, and ACSL3-Dependent Lipid Remodeling in Alzheimer's Disease

Background: The whey-derived tetrapeptide Gly-Thr-Trp-Tyr (GTWY; beta-lactolin) has a reported PHB2-dependent mitochondrial effect. Distinct studies connect PHB2 to iron-associated ferroptosis regulation and ACSL3-dependent lipid metabolism. Published ACSL3 degradation-associated ferroptosis in HT22 supports this neuronal-derived model, while direct PHB2 regulation of ACSL3 in neurons remains unestablished. These findings motivate a convergence hypothesis with separable biological predictions. Methods: We integrated an audited literature-relation core with a chemically defined L-GTWY panel. Stereocenters were Thr Ca S, Thr Cb R, Trp Ca S, and Tyr Ca S; the inputs retained 15 active torsions with rigid amides. Twenty AutoDock Vina 1.2.7 searches compared native zwitterionic GTWY and neutral Ac-GTWY-NH2 across five seeds per ligand in each H47-HID/HIE model, using identical receptor heavy coordinates, exhaustiveness 32, and a shared 32 A cubic box. We audited all 400 output modes and 880 rigid transfers of first-ranked poses to experimental PHB1/PHB2 assemblies. A separate, restrained Amber14/OBC2 minimization examined one 9O9Z-derived HID/capped-peptide complex. Prospective validation adds a capped mirror-image D-peptide comparator, protein-free lipid oxidation, and PHB2/ACSL3 suppression-rescue tests. Computational Findings: HID scores were -6.494 +- 0.320 kcal/mol for GTWY and -6.568 +- 0.054 kcal/mol for Ac-GTWY-NH2; HIE scores were -6.116 +- 0.305 and -6.611 +- 0.462 kcal/mol, respectively. Capped HID poses formed one <=2 A RMSD cluster (maximum 1.638 A), whereas capped HIE poses formed three clusters (maximum 9.987 A). For the selected 9O9Z/HID complex, minimization reduced maximum peptide-protein vdW-radius overlap from 0.872 to 0.183 A with peptide-backbone displacement of 0.550 A. Two D82-backbone hydrogen-bond candidates were geometrically compatible; no D82-carboxylate salt bridge was supported. Hypothesized Mechanism: GTWY may modulate accessible PHB2 pools and thereby influence mitochondrial quality control, ferritin-associated iron availability, and ACSL3-dependent oleate utilization. These branches may converge on ferroptosis resistance without changing in the same direction or contributing equally. Significance: Capped GTWY retained D82/D127-region localization and similar mean docking scores across the two neutral H47 models while exhibiting tautomer-sensitive pose heterogeneity. The package provides a hypothesis-generating computational report and a prospective, de-risked experimental protocol for laboratory validation.