A molecular dynamics study of adenylyl cyclase: the impact of ATP and G-protein binding

Adenylyl cyclases (ACs) catalyze the biosynthesis of cyclic adenosine monophosphate (cAMP) from adenosine triphosphate (ATP) and play an important role in many signal transduction pathways. The enzymatic activity of ACs is carefully controlled by a variety of molecules, including G-protein subunits that can both stimulate and inhibit cAMP production. Using homology models developed from existing structural data, we have carried out all-atom, microsecond-scale molecular dynamics simulations on the AC5 isoform of adenylyl cyclase and on its complexes with ATP and with the stimulatory G-protein subunit Gsα. The results show that both ATP and Gsα binding have significant effects on the structure and flexibility of adenylyl cyclase. New data on ATP bound to AC5 in the absence of Gsα notably help to explain how Gsα binding enhances enzyme activity and could aid product release. Simulations also suggest a possible coupling between ATP binding and interactions with the inhibitory G-protein subunit Gαi.

All-atom molecular dynamics simulations were performed with the GROMACS 5 package. The simulations were carried out in an NTP ensemble at a temperature of 310 K and a pressure of 1 bar using a Bussi velocity-rescaling thermostat  (t_T = 1 ps) and a Parrinello-Rahman barostat (t_P = 1 ps).  We provide the atomistic trajectories of the following 6 systems after 400 ns of equilibration:

• AC5
• AC5+ATP
• AC5+Gsα
• AC5+ATP+Gsα
• AC5+FOK
• AC5+ATP+FOK

In each trajectory, the frames are saved each 20 ps.