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How does the cAMP-dependent protein kinase catalyze the phosphorylation reaction: an ab initio QM/MM study.
J Am Chem Soc. 2005 Feb 09; 127(5):1553-62.JA

Abstract

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(2+) 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(2+) 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.

Authors+Show Affiliations

Howard Hughes Medical Institute, Department of Chemistry and Biochemistry and Department of Pharmacology, University of California at San Diego, La Jolla, CA 92093-0365, USA. ycheng@mccammon.ucsd.eduNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't
Research Support, U.S. Gov't, Non-P.H.S.
Research Support, U.S. Gov't, P.H.S.

Language

eng

PubMed ID

15686389

Citation

Cheng, Yuhui, et al. "How Does the cAMP-dependent Protein Kinase Catalyze the Phosphorylation Reaction: an Ab Initio QM/MM Study." Journal of the American Chemical Society, vol. 127, no. 5, 2005, pp. 1553-62.
Cheng Y, Zhang Y, McCammon JA. How does the cAMP-dependent protein kinase catalyze the phosphorylation reaction: an ab initio QM/MM study. J Am Chem Soc. 2005;127(5):1553-62.
Cheng, Y., Zhang, Y., & McCammon, J. A. (2005). How does the cAMP-dependent protein kinase catalyze the phosphorylation reaction: an ab initio QM/MM study. Journal of the American Chemical Society, 127(5), 1553-62.
Cheng Y, Zhang Y, McCammon JA. How Does the cAMP-dependent Protein Kinase Catalyze the Phosphorylation Reaction: an Ab Initio QM/MM Study. J Am Chem Soc. 2005 Feb 9;127(5):1553-62. PubMed PMID: 15686389.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - How does the cAMP-dependent protein kinase catalyze the phosphorylation reaction: an ab initio QM/MM study. AU - Cheng,Yuhui, AU - Zhang,Yingkai, AU - McCammon,J Andrew, PY - 2005/2/3/pubmed PY - 2005/3/23/medline PY - 2005/2/3/entrez SP - 1553 EP - 62 JF - Journal of the American Chemical Society JO - J Am Chem Soc VL - 127 IS - 5 N2 - 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(2+) 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(2+) 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. SN - 0002-7863 UR - https://www.unboundmedicine.com/medline/citation/15686389/How_does_the_cAMP_dependent_protein_kinase_catalyze_the_phosphorylation_reaction:_an_ab_initio_QM/MM_study_ L2 - https://doi.org/10.1021/ja0464084 DB - PRIME DP - Unbound Medicine ER -