How Does the cAMP-Dependent Protein Kinase Catalyze the Phosphorylation Reaction: An ab Initio QM/MM Study.
We have carried out density functional theory QM/MM calculations on the catalytic subunit of cAMP-dependent protein kinase (PKA). The QM/MM calculations indicate that the phosphorylation reaction catalyzed by PKA is mainly dissociative, and Asp166 serves as the catalytic base to accept the proton de...
| Publicado en: | Journal of the American Chemical Society Vol. 127; no. 5; pp. 1553 - 1563 |
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| Autores principales: | , , |
| Formato: | Artículo |
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American Chemical Society
2/9/2005
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| Acceso en línea: | Ver este registro en EBSCOhost |
| fields | @attributes: recordID: 1 pdfLink: plink: https://search.ebscohost.com/login.aspx?direct=true&db=hlh&AN=16097942&site=ehost-live header: @attributes: shortDbName: hlh uiTerm: 16097942 longDbName: Humanities International Complete uiTag: AN controlInfo: bkinfo: jinfo: jid: 00027863 ACS jtl: Journal of the American Chemical Society issn: 00027863 maglogo: N pubinfo: dt: 2/9/2005 vid: 127 iid: 5 pid: 997 pub: American Chemical Society artinfo: ui: 16097942 10.1021/ja0464084 ppf: 1553 ppct: 10 formats: tig: atl: How Does the cAMP-Dependent Protein Kinase Catalyze the Phosphorylation Reaction: An ab Initio QM/MM Study. aug: au: Cheng, Yuhui Zhang, Yingkai Mccammont, J. Andrew affil: University of California at San Diego. New York University. su: Protein kinases Phosphorylation Density functionals Chemical reactions Catalysis Molecular dynamics sug: subj: Protein kinases Phosphorylation Density functionals Chemical reactions Catalysis Molecular dynamics ab: We have carried out density functional theory QM/MM calculations on the catalytic subunit of cAMP-dependent protein kinase (PKA). The QM/MM calculations indicate that the phosphorylation reaction catalyzed by PKA is mainly dissociative, and Asp166 serves as the catalytic base to accept the proton delivered by the substrate peptide. Among the key interactions in the active site, the Mg ions, glycine rich loop, and Lys72 are found to stabilize the transition state through electrostatic interactions. On the other hand, Lys168, Asn171, Asp184, and the conserved waters bound to Mg ions do not directly contribute to lower the energy barrier of the phosphorylation reaction, and possible roles for these residues are proposed. The QM/MM calculations with different QM/MM partition schemes or different initial structures yield consistent results. In addition, we have carried out 12 ns molecular dynamics simulations on both wild type and K168A mutated PKA, respectively, to demonstrate that the catalytic role of Lys168 is to keep ATP and substrate peptide in the near-attack reactive conformation. pubtype: Academic Journal doctype: Article src: R language: English refInfo: copyright: @attributes: flag: Y dt: @attributes: year: 2005 holdings: @attributes: islocal: N |
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