Dimer-interface effects on tetramer stabilization and tryptophan dynamics in allosterically modulated TPH-II

Abstract

Tryptophan hydroxylase-II (TPH-II) controls the rate-limiting step of neuronal serotonin biosynthesis and plays a central role in neuropsychiatric health. As proper tetramer formation is essential for TPH-II stability and function, targeting its quaternary structure through allosteric modulation presents a promising yet still underexplored therapeutic strategy. In this study, we combined virtual screening, molecular dynamics simulations, and MMPBSA to identify ligands that bind at the interfacial A-D allosteric pocket of tetrameric human TPH-II. All the analyzed candidates, L1-L6 maintain the compact global conformations, as supported by RMSD, RMSF, PCA, FEL, and salt-bridge analyses. MM/PBSA analysis indicated that L2 exhibited the most favorable binding energy among the studied complexes, while in silico ADMET profiling suggested that L2 and L4 possess favorable CNS-compatible pharmacokinetic properties. Together, these findings provide insight into allosteric modulation of TPH-II and identify the A-D interface as a potential regulatory region contributing to tetramer integrity and highlighting L2 may serve as a candidate scaffold for further computational and experimental investigation in TPH-II functional regulation.