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Home / Equine Research Bank / Proc Natl Acad Sci U S A / Anticorrelated motions as a driving force in enzyme catalysi...
Proceedings of the National Academy of Sciences of the United States of America2004; 101(36); 13152-13156; doi: 10.1073/pnas.0405502101

Anticorrelated motions as a driving force in enzyme catalysis: the dehydrogenase reaction.

Abstract: Molecular dynamics and cross-correlation analysis of the horse liver alcohol dehydrogenase HLADH.NAD(+).PhCH(2)O(-) complex has established anticorrelated motions between the NAD(+)-binding domain and other portions of the enzyme. Four pairs of anticorrelated interactions are (i and ii) cofactor-binding domain: C(alpha) of V292 and the CG1 of V203 with C7 of PhCH(2)O(-); (iii) cofactor-binding domain: amide carbonyl oxygen of I318 with amide N of H67; and (iv) cofactor domain: C(alpha) of T178 with carbonyl oxygen of L141. The average distances between pairs are 9.2 A for i, 8.2 A for ii, 14.7 A for iii, and 18.2 A for iv. The motions of i and ii are most important in the approximately 0.5 A pushing of C4 of NAD(+) toward C7 of PhCH(2)O(-) to form push near-attack conformer (NACs). The motions of iv are less so, and those of iii are not important. Seventy-five quantum mechanics/molecular mechanics calculations of the energies of reaction were carried out without structural restrictions from different stages of the molecular dynamics trajectory. Of the 71 conformations, the 29 fulfilling NAC criteria were associated with the lowest energies of activation. Thus, anticorrelated motions from the NAD(+)-binding domain by way of the neighboring V292 and V203 have a pushing motion, which moves the C4 of NAD(+) toward the H-C7 of the substrate. Longer-range anticorrelated motions involving the cofactor-binding domain have no or very little influence on NAC formation.
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Publication Date: 2004-08-26 PubMed ID: 15331786PubMed Central: PMC516540DOI: 10.1073/pnas.0405502101Google Scholar: Lookup
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Summary

This research summary has been generated with artificial intelligence and may contain errors and omissions. Refer to the original study to confirm details provided. Submit correction.

The research paper investigates how anticorrelated motions—the movement of different parts of an enzyme in opposite directions—affect the process of enzyme catalysis in the horse liver alcohol dehydrogenase (HLADH) enzyme. Using detailed molecular analysis, the researchers found that these motions drive important processes that activate reactions within the enzyme.

Overview of the Research Methods

  • The researchers used molecular dynamics and cross-correlation analysis techniques to study the complex interactions within the HLADH enzyme.
  • Four pairs of anticorrelated interactions were identified. They involved movements between the cofactor-binding domain (a key area for the enzyme’s functions) and other sections of the enzyme.
  • The researchers performed multiple quantum mechanics/molecular mechanics calculations of the energies of reaction without structural restrictions during various stages of the molecular dynamic trajectories.

Key Findings

  • The movements between the NAD(+)-binding domain and other parts of the enzyme were found to be important for the initiation of reactions within the enzyme.
  • The researchers discovered that the anticorrelated movements drive a “pushing” motion, moving parts of the NAD(+) cofactor toward the substrate, facilitating the formation of the push ‘near-attack’ conformer (NACs) – key ‘ready-to-react’ configurations.
  • Of the 71 conformations studied, the 29 conformations that satisfied the NAC criteria were associated with the lowest energies of activation.
  • Longer-range anticorrelated motions involving the cofactor-binding domain were found to have little or no influence on NAC formation.

Implications of the Study

  • This study provides insights into the molecular mechanics of the HLADH enzyme, exploring how different parts interact and influence the overall functionality of the enzyme.
  • Understanding these anticorrelated movements could contribute to future initiatives aimed at modulation or manipulation of enzymatic processes, with potential applications in drug design and the management of metabolic disorders.

Cite This Article

APA
Luo J, Bruice TC. (2004). Anticorrelated motions as a driving force in enzyme catalysis: the dehydrogenase reaction. Proc Natl Acad Sci U S A, 101(36), 13152-13156. https://doi.org/10.1073/pnas.0405502101

Publication

Proceedings of the National Academy of Sciences of the United States of America
ISSN: 0027-8424
NlmUniqueID: 7505876
Country: United States
Language: English
Volume: 101
Issue: 36
Pages: 13152-13156

Researcher Affiliations

Luo, Jia
  • Department of Chemistry and Biochemistry, University of California, Santa Barbara, CA 93106, USA.
Bruice, Thomas C

    MeSH Terms

    • Alcohol Dehydrogenase / chemistry
    • Alcohol Dehydrogenase / metabolism
    • Animals
    • Binding Sites
    • Catalysis
    • Horses
    • Liver / enzymology

    Grant Funding

    • R37 DK009171 / NIDDK NIH HHS
    • 5R37DK09171-38 / NIDDK NIH HHS

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