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Molecular Dynamics Simulations of NAD⁺-Induced Domain Closure in Horse Liver Alcohol Dehydrogenase

Steven Hayward ^* and Akio Kitao  

^* School of Computing Sciences and School of Biological Sciences, University of East Anglia, Norwich, NR4 7TJ, United Kingdom; Institute of Molecular and Cellular Biosciences, The University of Tokyo, Tokyo 113-0032, Japan; and Core Research for Evolutional Science and Technology, 1-1-1 Yayoi, Bunkyo, Tokyo 113-0032, Japan

Correspondence: Address reprint requests to Dr. Steven Hayward, School of Computing Sciences and School of Biological Sciences, University of East Anglia, Norwich, NR4 7TJ, UK. Tel.: 44-1603-593542; Fax: 44-1603-593345; E-mail: sjh{at}cmp.uea.ac.uk.

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.

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