Integration of inhibition kinetics and molecular dynamics simulations to determine the effects of Zn2+ on acetaldehyde dehydrogenase 1

•The inhibitory effect of Zn2+ on acetaldehyde dehydrogenase 1 (ALDH1).•Integrating study between kinetics and computational molecular dynamics simulations.•Zn2+ ligand binding mechanisms to ALDH1.•Zn2+ potent application for ALDH1-associated human diseases.

Understanding the mechanism of inhibition of acetaldehyde dehydrogenase 1 (ALDH1) is clinically important because this enzyme is involved in several types of cancers and other diseases. In this study, we investigated the effects of Zn2+ on the structure of ALDH1 by integrating kinetic inhibition studies with computational simulations. Tertiary structure and hydrophobic surface changes were also assessed by measuring intrinsic and ANS-binding fluorescence. The crystallographic structure of ALDH1 was applied in computational docking as well as molecular dynamics simulations. We found that the direct binding of Zn2+ to ALDH1 induces structural changes and inhibits ALDH1 activity. Moreover, Zn2+-mediated inactivation of ALDH1 was associated with structural changes. Specifically, beta regions of ALDH1 were exposed upon binding of Zn2+ and underwent significant conformational changes, including the loss of beta secondary structure. Our study provides insight into the structural changes that accompany Zn2+-mediated inhibition of ALDH1. Our findings also suggest that Zn2+, a potent inhibitor of ALDH1, may be useful in the treatment of ALDH1-related diseases.

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