Abstract
Functions of biomolecules, in particular enzymes, are usually modulated by structural fluctuations. This is especially the case in a gated diffusion-controlled reaction catalyzed by an enzyme such as acetylcholinesterase. The catalytic triad of acetylcholinesterase is located at the bottom of a long and narrow gorge, but it catalyzes the extremely rapid hydrolysis of the neurotransmitter, acetylcholine, with a reaction rate close to the diffusion-controlled limit. Computational modeling and simulation have produced considerable advances in exploring the dynamical and conformational properties of biomolecules, not only aiding in interpreting the experimental data, but also providing insights into the internal motions of the biomolecule at the atomic level. Given the remarkably high catalytic efficiency and the importance of acetylcholinesterase in drug development, great efforts have been made to understand the dynamics associated with its functions by use of various computational methods. Here, we present a comprehensive overview of recent computational studies on acetylcholinesterase, expanding our views of the enzyme from a microstate of a single structure to conformational ensembles, strengthening our understanding of the integration of structure, dynamics and function associated with the enzyme, and promoting the structure-based and/or mechanism-based design of new inhibitors for it.
Highlights
Alzheimer’s disease (AD) is a neurodegenerative disorder associated with impairments in cholinergic transmission that leads to memory loss [1]
The gorge size was quantified with a single variable, the gorge radius, ρ(t), for snapshots recorded every picosecond from the Molecular dynamics (MD) trajectory
MD simulations of mAChE in complex with FAS2 showed that the Ω-loop undergoes a flexible rearrangement during which some of its secondary structure rapidly changes from a coil to a 310 or α helical segment [38]
Summary
Alzheimer’s disease (AD) is a neurodegenerative disorder associated with impairments in cholinergic transmission that leads to memory loss [1]. Because of its narrow cross-section, substrates and inhibitors with a much larger cross-section than the bottleneck would have no access to the catalytic site if the enzyme were rigid This intrinsic property is shared by AChEs from other species such as mouse [7] and human [8] AChEs, due to their high sequence similarity to TcAChE, including especially high conservation of residues inside the gorge (Figure 1c). In addition to the conventional MD simulations, several modified simulation methodologies or strategies have been employed, including multiple parallel nanosecond MD simulations, multiple copy sampling, umbrella sampling, steered MD simulation, targeted MD simulation, and metadynamics simulation These allow more efficient exploration of AChE's conformational space, so as to study ligand binding to and/or release from AChE, as well as the dynamic features of oligomeric AChE. Clustalx [16] and the ENDscript server [17]
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