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

Abstract

We used molecular dynamics to find the average path of the A-domainH→Bconformational 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 representsH→Btransition 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 andβ-subdomain. Taken together, events B, E, and D correspond to the hinge movement towardsβ-barrel. Transition of B/C-helix turn (a.a. 229–234) fromα-form toπ-form accounts for event F. Event G implies thatπ-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 Iαmay contribute to new approaches to designing pharmaceuticals based on cAMP analogs.