Molecular basis of chemical chaperone effects of N-octyl-β-valienamine on human β-glucosidase in low/neutral pH conditions

Hiroyuki Jo, Katsuyuki Yugi, Seiichiro Ogawa, Yoshiyuki Suzuki, Yasubumi Sakakibara

研究成果: Article査読

17 被引用数 (Scopus)


Chemical chaperone therapy is a strategy for restoring the activities of mutant lysosomal hydrolases. This therapy involves chemical compounds binding to the dysfunctional enzymes. The chemical chaperones for lysosomal hydrolases are anticipated to stabilize folding of target enzymes by binding at neutral pH and rescuing enzyme activities by dissociation in acidic conditions after transport to lysosome. However, the molecular basis describing the mechanism of action of chemical chaperones has not been analysed sufficiently. Here we present results derived from molecular dynamics simulations showing that the binding free energy between human β-glucosidase and its known chemical chaperone, N-octyl-β-valienamine (NOV), is lower at pH 7 than at pH 5. This observation is consistent with the hypothetical activity of chemical chaperones. The pH conditions were represented as differences in the protonation states of ionizable residues which were determined from predicted pKa values. The binding free energy change is negatively correlated to the number of hydrogen bonds (H-bonds) formed between GLU235, the acid/base catalyst of the enzyme, and the N atom of NOV. At pH 7, NOV is inserted further into the active site than at pH 5. Consequently, this provides an increase in the number of H-bonds formed. Thus, we conclude that the dissociation of NOV from β-glucosidase at pH 5 occurs due to an increase in the binding free energy change caused by protonation of several residues which decreases the number of H-bonds formed between NOV and the enzyme.

ジャーナルJournal of Proteomics and Bioinformatics
出版ステータスPublished - 2010 4月

ASJC Scopus subject areas

  • 生化学
  • 分子生物学
  • コンピュータ サイエンスの応用
  • 細胞生物学


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