TY - JOUR T1 - The Dynamical Mechanism of Auto-Inhibition of AMP-Activated Protein Kinase A1 - Peng, Cheng A1 - Head-Gordon, Teresa Y1 - 2011/07/21 N2 - Author Summary AMP-activated protein kinase (AMPK) maintains the balance between ATP production and energy consumption in eukaryotic cells by responding to the rise of intracellular AMP. We report on a novel method that uses normal mode analysis of an elastic network model drawn from microsecond all-atom molecular dynamics simulations to analyze the activation mechanism of the AMPK homolog SNF1, which is believed to have the same mechanism as mammalian AMPK. There has been important new X-ray crystallographic and mutagenesis information on the self-regulation of AMPK based on its auto-inhibitory domain, although that view is primarily static. We provide a dynamical analysis to show that AID inhibits catalytic function by restraining KD into an unproductive open conformation and limiting functional local structural rearrangement, and that mutations that disrupt the interactions between the KD and AID free the KD to undergo both the global interlobe conformational transition and functional local structural rearrangement. This suggests new ways in which drugs might be used to regulate this important molecular machine. JF - PLOS Computational Biology JA - PLOS Computational Biology VL - 7 IS - 7 UR - https://doi.org/10.1371/journal.pcbi.1002082 SP - e1002082 EP - PB - Public Library of Science M3 - doi:10.1371/journal.pcbi.1002082 ER -