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

Proceedings of the National Academy of Sciences of the United States of America
Jia Luo, Thomas C Bruice

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 ...Continue Reading

References

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Citations

Dec 24, 2013·Chemical Reviews·Joshua P Layfield, Sharon Hammes-Schiffer
Feb 15, 2008·The Journal of Physical Chemistry. B·Sten O Nilsson LillGrover L Waldrop
Jun 8, 2006·Annual Review of Biochemistry·Sharon Hammes-Schiffer, Stephen J Benkovic
Nov 18, 2004·Proceedings of the National Academy of Sciences of the United States of America·Brian J Bahnson
Feb 21, 2006·Proceedings of the National Academy of Sciences of the United States of America·Sagar D Khare, Nikolay V Dokholyan
Sep 11, 2007·Biophysical Journal·Marilisa NeriPaolo Carloni
Nov 9, 2005·Current Opinion in Structural Biology·Vern L Schramm
May 20, 2008·Biophysical Journal·Agustí EmperadorModesto Orozco
Dec 23, 2017·Protein Science : a Publication of the Protein Society·Karthik K ShanmuganathamBryce V Plapp
Aug 10, 2006·Chemical Reviews·Zachary D Nagel, Judith P Klinman
Dec 9, 2008·Journal of Chemical Theory and Computation·Agustí EmperadorModesto Orozco
Jul 9, 2009·Archives of Biochemistry and Biophysics·Bryce V Plapp

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