Acetylcholinesterase: Structure, dynamics, and interactions with organophosphorus compounds

Hung, Li‐Wei; Sanbonmatsu, Karissa Yoshiko; Williams, Robert F.; Chen, Julian C.‐H.

doi:10.1002/pro.70297

Acetylcholinesterase: Structure, dynamics, and interactions with organophosphorus compounds

Journal Article · Fri Sep 19 00:00:00 EDT 2025 · Protein Science

DOI:https://doi.org/10.1002/pro.70297· OSTI ID:3001293

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Los Alamos National Laboratory (LANL), Los Alamos, NM (United States)

Acetylcholinesterase (AChE) is an enzyme that hydrolyzes the neurotransmitter acetylcholine (ACh), removing it from the synaptic cleft after the transmission of an electrical signal, making it an essential component of chemical neurotransmission. AChE is a serine hydrolase, containing a catalytic triad of Ser/His/Glu. AChE is a prime target for pharmaceuticals treating a variety of neurological disorders. It is also the target of synthetic organophosphorus (OP) compounds that have been used as pesticides and chemical warfare agents. OP compounds contain a potent leaving group, such as fluorine, and act by forming a covalent adduct with the catalytic serine of the AChE active site. A wealth of structural information is available for AChE, including over 300 structures, including a subset of structures in complex with drugs as well as OP compounds. This review will highlight the interactions between OP compounds and AChE from a structural and computational perspective, with a discussion of access to the active site, as well as side reactions that lead to dealkylation of the OP-catalytic serine adduct, a process known as aging. We conclude that while the majority of the conformational changes needed to accommodate the OP compounds are localized to the acyl loop in the crystal structures, molecular dynamics simulations highlight the potential for a far more dynamic enzyme.

View Accepted Manuscript (DOE)

Research Organization:: Los Alamos National Laboratory (LANL), Los Alamos, NM (United States)

Sponsoring Organization:: USDOE Laboratory Directed Research and Development (LDRD) Program; USDOE National Nuclear Security Administration (NNSA)

Grant/Contract Number:: 89233218CNA000001

OSTI ID:: 3001293

Report Number(s):: LA-UR--25-24767; 10.1002/pro.70297

Journal Information:: Protein Science, Journal Name: Protein Science Journal Issue: 10 Vol. 34; ISSN 0961-8368; ISSN 1469-896X

Publisher:: Wiley -- The Protein SocietyCopyright Statement

Country of Publication:: United States

Language:: English

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59 BASIC BIOLOGICAL SCIENCES
acetylcholinesterase
molecular dynamics
nerve agent
organophosphorus
protein dynamics
structure

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