Authors:

Shreya Krishnan

Date Created:

Not specified

Course Title:

Professor:

Not specified

About Paper:

Mammalian adenylyl cyclase isoform 1 (AC1), which synthesizes the cell signaling molecule cyclic adenosine monophosphate (cAMP), is key in synaptic plasticity and long-term chronic pain syndromes, and it is linked to drug abuse. Understanding mechanisms governing AC1 behavior can improve drug development for multiple disease pathways. The protein calmodulin (CaM) and the small molecule forskolin (Fsk) stimulate AC1. Per prior research, CaM can preserve AC1 function when the AC1 Fsk binding pocket contains mutations. As no direct contacts exist between CaM and Fsk binding pockets, this suggests that CaM and Fsk binding cause global conformational changes to AC1; however, such mechanisms have not been investigated. This study developed a computational model for AC1 to determine how the cofactors CaM and Fsk individually and jointly affect AC1 structure, and whether the joint effect of the cofactors differs from the individual effects. Four systems were simulated using Desmond Molecular Dynamics simulations: AC1 bound to no cofactors, AC1- CaM, AC1-Fsk, and AC1-CaM-Fsk. Visualization of vectors quantifying movement through each simulation demonstrated that CaM and Fsk reduced movement of the binding region for AC1 substrate, increasing stability of interactions and elucidating a possible mechanism of AC1 activation. Principal component analysis visualizations and contributions of amino acids to key AC1 movements will be compared to investigate the synergistic effects of CaM and Fsk on AC1 structure and activity. By ascertaining the underlying mechanisms of AC1 protein-protein interactions, these findings can provide new drug targets for novel treatments for AC1- associated diseases including migraines, inflammation, and drug abuse. Keywords: Adenylyl Cyclase 1; Forskolin; Calmodulin; Molecular Dynamics

Source:

Purdue University / 2024

Topics:

No topics listed

Co-authors:

Shreya Krishnan