Combining electronic structure methods with the calculation of hydrogen vibrational wavefunctions: Application to hydride transfer in liver alcohol dehydrogenase

Simon P. Webb, Pratul K. Agarwal, Sharon Hammes-Schiffer

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This paper presents an application of a computational approach combining electronic structure methods with the calculation of hydrogen vibrational wavefunctions. This application is directed at elucidating the nature of the nuclear quantum mechanical effects in the oxidation of benzyl alcohol catalyzed by liver alcohol dehydrogenase (LADH). The hydride transfer from the benzyl alcohol substrate to the NAD+ cofactor is described by a 148-atom model of the active site. The hydride potential energy curves and the associated hydrogen vibrational wavefunctions are calculated for structures along minimum energy paths and straight-line reaction paths obtained from electronic structure calculations at the semiempirical PM3 and ab initio RHF/3-21G levels. The results indicate that, for these levels of theory, the hydride transfer is adiabatic and hydrogen tunneling does not play a critical role along the minimum energy path. In contrast, nonadiabatic effects and hydrogen tunneling are shown to be important along the more relevant straight-line reaction paths. The secondary hydrogens were found to be significantly coupled to the transferring hydride near the transition state. In addition, the puckering of the NAD+ ring was found to be a dominant contribution to the reaction coordinate near the transition state. Further from the transition state, the reaction coordinate is a mixture of many heavy-atom modes, including the donor-acceptor distance and the distance between the substrate and the neighboring zinc and serine residue. These results imply that hydrogen tunneling in LADH is strongly impacted by the puckering of the NAD+ ring (which modulates the asymmetry of the hydride potential energy curve) and the distance between the donor and acceptor carbons (which modulates the barrier of the hydride potential energy curve).

Original languageEnglish (US)
Pages (from-to)8884-8894
Number of pages11
JournalJournal of Physical Chemistry B
Issue number37
StatePublished - Sep 21 2000


ASJC Scopus subject areas

  • Physical and Theoretical Chemistry
  • Surfaces, Coatings and Films
  • Materials Chemistry

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