Computational Studies on Acetylcholinesterases

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.

Hot Spots for Protein Partnerships at the Surface of Cholinesterases and Related α/β Hydrolase Fold Proteins or Domains—A Structural Perspective

“…An antiparallel architecture of the tetramerization domain was subsequently approached through the superhelical structure of an antiparallel PRAD-WAT complex made from synthetic peptides in a 1:4 molar ratio [ 55 ]. Together, these data provided complementary bases for exploration of the tetramer coordination by molecular modeling and dynamics simulations [ 56 , 57 ] (for a review see [ 17 ] in this issue). Other tetrameric assemblies were observed in crystal structures solved from recombinant monomers of AChE, which however formed canonical dimers ([ 58 ] and further analyzed in [ 56 ]), or of BChE, which formed non-canonical dimers [ 46 ] (see above), but experimental in vitro data that would support them physiologically are not available.…”

“…Transient opening of a back door channel connecting the active center to the outside solvent, but distinct from the active center gorge, was proposed as a molecular mechanism contributing to the AChE high catalytic efficiency [ 81 ]. Concerted positional rearrangements of several residues in this region, including shutter-like motions of aromatic side chains forming a thin wall between the active center and the bulk, were then evidenced through combined structural and molecular dynamics simulation studies [ 82 , 83 , 84 ] (for a review see [ 17 ] in this issue). In turn, observation of open channels in the back door regions of crystalline DmAChE, aflatoxin-bound TcAChE and Fab410-bound BfAChE [ 40 , 85 , 86 ] and of substrate molecules bound in this surface region in a mAChE inactive mutant [ 87 ] led to support existence of a back door in AChE.…”

“…In addition to its “classical” role in terminating synaptic transmission, AChE is proposed to play non-classical roles including cell adhesion, neurite outgrowth through recognition of laminin [ 15 ] and potentiation of amyloid-β peptide nucleation into pathogenic fibrils [ 16 ] (for a review see [ 3 ]). Experimental evidences obtained in vitro or in cellula for involvement of the PAS along with computational studies have been reported, but no experimental structural data are available (for a review see [ 17 ] in this issue).…”

Steady-State Kinetics of Enzyme-Catalyzed Hydrolysis of Echothiophate, a P–S Bonded Organophosphorus as Monitored by Spectrofluorimetry

“…Nevertheless, molecular docking often provides useful clues about molecular interactions and it is helpful for comparative studies, as in the present report. Furthermore, there is a body of docking studies about numerous ligands into ChEs, coupled with experimental measurements, serving refinement of this approach [32,33]. Also, substantial efforts have been made to parametrize metal-containing systems [34,35] to provide adequate docking score.…”

Erratum: Xu, Y., et al. Computational Studies on Acetylcholinesterases. Molecules 2017, 22, 1324.

“…The Molecules Editorial Office wishes to make the following erratum to this paper [ 1 ]. There is a typing error in the catalytic triad of Tc AChE within the text (line 9, page 2) as well as in the legend of Figure 1 (line 6 from the bottom, page 3).…”