Synergistic Interplay of Stimulatory Cofactors in the Activation of Adenylyl Cyclase Isoform 1

Adenylyl Cyclase
isoform 1 (AC1), responsible for synthesizing
the signaling molecule cyclic adenosine monophosphate (cAMP), is key
in synaptic plasticity, long-term chronic pain syndromes, osteosarcoma-associated
pain, and drug abuse. The protein calmodulin (CaM) and the small molecule
forskolin (Fsk) stimulate AC1 to form a catalytic site for ATP catalysis;
however, molecular AC1 structural changes triggered by CaM and Fsk
remain poorly understood. This study developed a computational model
for AC1–cofactor complexes and used all-atom molecular dynamics
(MD) simulations to determine how CaM and Fsk individually and jointly
affect AC1 dynamics and assess whether they exhibit any synergistic
effects. Four systems were investigated: AC1-No Partner, AC1-CaM,
AC1-Fsk, and AC1-CaM-Fsk. Simulations revealed that individual and
joint cofactor bindings induced unique structural changes within the
regulatory C1b subdomain of AC1. CaM and Fsk binding result in a reduced
cross section of the catalytic site, implying tighter binding for
ATP. Notably, the results showed that the AC1-CaM-Fsk system exhibited
unique features distinct from the AC1-CaM and AC1-Fsk systems, demonstrating
synergistic effects of CaM and Fsk. Our understanding of AC1-cofactor
interactions can guide future research toward modulating AC1 activity,
potentially contributing to the development of novel treatments for
AC1-associated diseases.