Gorge Motions of Acetylcholinesterase Revealed by Microsecond Molecular Dynamics Simulations

Abstract

Acetylcholinesterase, with a deep, narrow active-site gorge, attracts enormous interest due to its particularly high catalytic efficiency and its inhibitors used for treatment of Alzheimer’s disease. To facilitate the massive pass-through of the substrate and inhibitors, “breathing” motions to modulate the size of the gorge are an important prerequisite. However, the molecular mechanism that governs such motions is not well explored. Here, to systematically investigate intrinsic motions of the enzyme, we performed microsecond molecular dynamics simulations on the monomer and dimer of Torpedo californica acetylcholinesterase (TcAChE) as well as the complex of TcAChE bound with the drug E2020. It has been revealed that protein-ligand interactions and dimerization both keep the gorge in bulk, and opening events of the gorge increase dramatically compared to the monomer. Dynamics of three subdomains, S3, S4 and the Ω-loop, are tightly associated with variations of the gorge size while the dynamics can be changed by ligand binding or protein dimerization. Moreover, high correlations among these subdomains provide a basis for remote residues allosterically modulating the gorge motions. These observations are propitious to expand our understanding of protein structure and function as well as providing clues for performing structure-based drug design.

Synergistic Effects of Curcumin and Piperine as Potent Acetylcholine and Amyloidogenic Inhibitors With Significant Neuroprotective Activity in SH-SY5Y Cells via Computational Molecular Modeling and in vitro Assay

“…From the greater number of atoms in the bigger ligands, it was initially assumed that they were able to form more interactions that could contribute to greater stabilization with the receptor. However, in this case, since the CAS binding site is located at the base of a ~20-Å-deep and ~5-Å-narrow gorge (Cheng et al, 2017), it is believed that the limited space within the binding cavity was unable to accommodate the larger structures of bacoside A and chebulinic acid, causing the ligands to adopt unfavorable conformations, hence the poorer score. Another postulation for bacoside A and chebulinic acid to have higher binding energies can be due to their abilities to bind and interact with either CAS or PAS at a time instead of simultaneously as seen in the interactions of curcumin and piperine towards AChE.…”

“…In addition, insights into the bottleneck structure at the AChE gorge entrance have shown that even endogenous ACh substrate could only cross the narrowest portion when the gate opens momentarily (Henchman et al, 2002; Cheng et al, 2017). In light of this transient entry mechanism, we presume that an inhibitor ligand with dual-site binding capability would be a more potent and efficacious drug compared to ligands that bind to either site only, by reasoning that the former would only need to cross the gate once.…”

Computational Studies on Acetylcholinesterases

“…The resulting average gorge radius was 1.5 Å. ρ(t) was restricted within a range of 0.8 to 2.4 Å, with a standard deviation of 0.26 Å [ 20 ]. Very recently, microsecond MD simulations of the Tc AChE-E2020 complex and/or of the Tc AChE dimer have shown that the occupancy of the open state of the gorge increased from 0.2% in the monomer to 13.8% in the complex, to 20.6% and 17.5% in the two chains of the apo dimer, and to 50.5% and 40.6% in the two chains of the E2020-complexed dimer [ 21 ]. The effects of ligand binding and dimerization on gorge motions seem to be cooperative, since the largest occupancy of the open state was seen in the complexed dimer.…”

Therapeutic potency of substituted chromones as Alzheimer’s drug: Elucidation of acetylcholinesterase inhibitory activity through spectroscopic and molecular modelling investigation

“…Recent molecular dynamics (MD) simulation results revealed the crystal structure of AChE protein to be significantly different from its equilibrium structure in the solvent. 41 In this work, extensive MD simulations were carried out on the protein structure in aqueous medium to equilibrate it. Gromacs 5.1.2 package was used for the simulations, 42 utilizing AMBER99SB force field.…”