Tryptophan hydroxylase (TPH) is the rate-limiting enzyme in serotonin biosynthesis and exists as two isoforms, TPH1 and TPH2.  In the central nervous system, TPH2 is the predominant isoform and is exclusively expressed. TPH2 has an N-terminal regulatory domain (NRD) (amino acids 2 - 44) that is thought to repress its own synthesis, while TPH1 lacks NRD.
    In this study, we predicted the folding process of NRD using molecular dynamics packages Amber16. The folding of the complete amino acid sequence of NRD (WT) was compared with that of a partially shortened sequence of NRD (DEL) with a deletion of amino acids 36 - 85 encoded by EXON2.
    We used the radius of gyration for the folding evaluation, an index of polypeptides spread from the center of gravity. The radius of gyration of the WT structure converged at 60-90 ns from initial structures, whereas that of the DEL structure converged at less than 30 ns.
    After 200 ns from initial structures, the sufficiently converged structure of DEL was different from WT. Therefore, it is predicted that the translational repression via DEL is attenuated or negated compared with WT.  In this context, it is conceivable that EXON2 skipping induces an increase in TPH2 protein levels and consequently up-regulates biosynthesis of serotonin.