JUN 12, 2025

Molecular Basis of Adenylyl Cyclase 1 Activation Revealed by MD Simulations

Abstract:

Mammalian adenylyl cyclase isoform 1 (AC1) synthesizes the cell signaling molecule cyclic adenosine monophosphate (cAMP) in the brain. It plays a key role in synaptic plasticity and chronic pain syndromes and is linked to drug abuse. In this study, we used Molecular Dynamics (MD) simulations in the Desmond program to understand the molecular mechanisms that govern AC1 behavior in various disease pathways. AC1 activation is stimulated by the calmodulin (CaM) protein and a small molecule cofactor forskolin (Fsk), but such mechanisms have not been thoroughly investigated. As no direct contact exists between the CaM and Fsk binding pockets, the mechanism of their induced conformational changes in AC1 needs to be understood. To fill these knowledge gaps, we developed a computational model for AC1 to determine how the cofactors CaM and Fsk affect AC1 structure individually and jointly, and whether their combined effects differ from the individual effects. Four systems of the cytosolic region of AC1 were simulated: AC1 without cofactors, AC1-CaM, AC1-Fsk, and AC1-CaM-Fsk. The truncated cytosolic system was validated by comparison to a simulation of transmembrane AC1 bound to no partners, which indicated similar movement patterns in AC1 between the truncated and full systems. Analysis of AC1 binding pocket movement demonstrated that Fsk and CaM bring the two catalytic domains of AC1 closer together, facilitating ATP binding. Additionally, CaM binding allosterically increased the stability of the Fsk binding pocket, providing a mechanism for how CaM binding preserves AC1-Fsk interactions. With a clear understanding of AC1-CaM-Fsk interactions, future research can be directed toward designing small molecules and antibodies that modulate AC1 activation, potentially leading to novel treatments for AC1-associated diseases such as migraines, inflammation, and drug abuse.