Molecular Basis of Chemical Chaperone Effects of N-octyl-ÃÂ²-valienamine on Human ÃÂ²-glucosidase in Low/neutral pH Conditions
- *Corresponding Author:
- Dr. Yasubumi Sakakibara
Department of Biosciences and Informatics
Faculty of Science and Technology, Keio University
3-14-1 Hiyoshi, Kohoku-ku, Yokohama 223-8522, Japan
E-mail: [email protected]
Received Date: February 10, 2010; Accepted Date: March 22, 2010; Published Date: March 22, 2010
Citation: Jo H, Yugi K, Ogawa S, Suzuki Y, Sakakibara Y (2010) Molecular Basis of Chemical Chaperone Effects of N-octyl-β-valienamine on Human β-glucosidase in Low/neutral pH Conditions. J Proteomics Bioinform 3: 104-112. doi: 10.4172/jpb.1000128
Copyright: © 2010 Jo H, et al. This is an open-access Article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
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 ?-glucosidase and its known chemical chaperone, N-octyl-?-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 ?-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.