Molecular dynamics simulations of NAD(+)-induced domain closure in horse liver alcohol dehydrogenase

Hayward, Steven ORCID: and Kitao, Akio (2006) Molecular dynamics simulations of NAD(+)-induced domain closure in horse liver alcohol dehydrogenase. Biophysical Journal, 91 (5). pp. 1823-1831.

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Horse liver alcohol dehydrogenase is a homodimer, the protomer having a coenzyme-binding domain and a catalytic domain. Using all available x-ray structures and 50 ns of molecular dynamics simulations, we investigated the mechanism of NAD+-induced domain closure. When the well-known loop at the domain interface was modeled to its conformation in the closed structure, the NAD+-induced domain closure from the open structure could be simulated with remarkable accuracy. Native interactions in the closed structure between Arg369, Arg47, His51, Ala317, Phe319, and NAD+ were seen to form at different stages during domain closure. Removal of the Arg369 side-chain charge resulted in the loss of the tendency to close, verifying that specific interactions do help drive the domains closed. Further simulations and a careful analysis of x-ray structures suggest that the loop prevents domain closure in the absence of NAD+, and a cooperative mechanism operates between the subunits for domain closure. This cooperative mechanism explains the role of the loop as a block to closure because in the absence of NAD+ it would prevent the occurrence of an unliganded closed subunit when the other subunit closes on NAD+. Simulations that started with one subunit open and one closed supported this.

Item Type: Article
Faculty \ School: Faculty of Science > School of Biological Sciences
Faculty of Science > School of Computing Sciences
UEA Research Groups: Faculty of Science > Research Groups > Computational Biology
Depositing User: EPrints Services
Date Deposited: 01 Oct 2010 13:38
Last Modified: 22 Apr 2023 01:24
DOI: 10.1529/biophysj.106.085910

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