Insight into Acetylcholinesterase (AChE) conformations and dynamics as it relates to reactant capture and product release
Alisha Baral
Mentor: Dr. Brian Bennion, Biochemical and Biophysical Systems Group, Lawrence Livermore National Laboratory.
Date/Time: August 21st, 2025 at 3:00 PM.
Abstract: Acetylcholinesterase (AChE) is an essential enzyme in neurotransmission and the primary target of organophosphate (OP) nerve agents, whose recent use in civilian attacks underscores the urgent need for improved therapeutic strategies. Current treatments, such as oxime based reactivators, are limited by poor blood–brain barrier penetration, variable efficacy, and potential off-target side effects that have hindered the development of new approved antidotes. To support therapeutic design, it is critical to better understand the conformational dynamics of AChE, particularly the structural mechanisms underlying substrate entry and product release, which remains incompletely understood.
Several pathways, including the catalytic gorge, back door, and side door, have been proposed as possible routes for substrate and product trafficking through computational studies. However, the relative feasibility of these pathways under physiologically relevant conditions remains unresolved.
In this project, we employ molecular dynamics (MD) simulations of human AChE under different states and environments to investigate the conformational dynamics that regulate active-site accessibility. Using newly generated trajectories, we analyze loop and domain stability, fluctuations of key structural motifs, and gating behavior of proposed exits quantified by cross-sectional areas. Distance-based metrics were also examined to provide a framework for tracking ligand positioning relative to these putative pathways.
By comparing trajectories and probing different system conditions we assess the reproducibility and plausibility of specific release routes. Together, these analyses offer new insight into the conformational plasticity of AChE and the mechanistic basis of substrate and product trafficking, advancing our understanding of its catalytic cycle and help inform the design of next-generation therapeutics capable of overcoming the limitations of current treatments for nerve agent toxicity