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BioMed Research International
Volume 2017, Article ID 5846073, 7 pages
Research Article

Electrostatic Switch Function in the Mechanism of Protein Kinase A I Activation: Results of the Molecular Dynamics Simulation

1St. Petersburg State University, Universitetskaya nab. 7/9, St. Petersburg 199034, Russia
2Pavlov Institute of Physiology, Russian Academy of Sciences, nab. Makarova 6, St. Petersburg 199034, Russia
3Kyoto Sangyo University, Kamigamo-Motoyama, Kita-ku, Kyoto 603-8555, Japan

Correspondence should be addressed to Alexander A. Tokmakov; and Vasiliy E. Stefanov; ur.liam@fetsav

Received 6 November 2016; Revised 22 January 2017; Accepted 7 February 2017; Published 7 March 2017

Academic Editor: Serdar Kuyucak

Copyright © 2017 Olga N. Rogacheva et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.


We used molecular dynamics to find the average path of the A-domain conformational transition in protein kinase A Iα. We obtained thirteen productive trajectories and processed them sequentially using factor and cross-correlation analyses. The conformational transition is presented as partly deterministic sequence of six events. Event B represents transition of the phosphate binding cassette. Main participants of this event form electrostatic switch cAMP(O6)–A202(N-H)–G199(C=O). Through this switch, cAMP transmits information about its binding to hydrophobic switch L203–Y229 and thus triggers conformational transition of A-domain. Events C and D consist in N3A-motif displacement towards phosphate binding cassette and B/C-helix rotation. Event E involves an increase in interaction energy between Y229 and β-subdomain. Taken together, events B, E, and D correspond to the hinge movement towards β-barrel. Transition of B/C-helix turn (a.a. 229–234) from α-form to π-form accounts for event F. Event G implies that π-helical turn is replaced by kink. Emerging in the resulting conformation, electrostatic interaction R241–E200 facilitates kink formation. The obtained data on the mechanism of cAMP-dependent activation of PKA Iα may contribute to new approaches to designing pharmaceuticals based on cAMP analogs.