Dynamics of human acetylcholinesterase bound to non-covalent and covalent inhibitors shedding light on changes to the water network structure

Abstract

We investigated the effects of non-covalent reversible and covalent irreversible inhibitors on human acetylcholinesterase and human butyrylcholinesterase. Remarkably a non-covalent inhibitor, Huperzine A, has almost no effect on the molecular dynamics of the protein, whereas the covalently binding nerve agent soman renders the molecular structure stiffer in its aged form. The modified movements were studied by incoherent neutron scattering on different time scales and they indicate a stabilization and stiffening of aged human acetylcholinesterase. It is not straightforward to understand the forces leading to this strong effect. In addition to the specific interactions of the adduct within the protein, some indications point towards an extensive water structure change for the aged conjugate as water Bragg peaks appeared at cryogenic temperature despite an identical initial hydration state for all samples. Such a change associated to an apparent increase in free water volume upon aging suggests higher ordering of the hydration shell that leads to the stiffening of protein. Thus, several additive contributions seem responsible for the improved flexibility or stiffening effect of the inhibitors rather than a single interaction.

Thermodynamics of lipid multi-lamellar vesicles in presence of sterols at high hydrostatic pressure

“…The summed elastic intensities are inversely proportional to the root of the MSD 35 . The MSD are associated with the dynamic flexibility of the molecules and are a measure of the fluctuations in this temperature region, as explained in more details in a publication by M. Rheinstädter et al .…”

Computational Studies on Acetylcholinesterases

“…The similarity can be ascribed to the similar local surface topology and surface chemical composition of these four proteins. However, the dynamics of the water network was influenced by binding of a non-covalent inhibitor, HupA, or a covalent inhibitor, soman, to the active site of h AChE [ 46 ]. Soman forms a covalent bond with the catalytic serine of h AChE.…”

“…This conjugate undergoes a spontaneous dealkylation called “aging” that leads to the establishment of a stabilizing salt bridge between the aged phosphonate moiety and the protonated active-site histidine [ 47 ]. Such a salt bridge makes the enzyme more stabilized or stiff, and is accompanied by release of free water molecules, so that it indirectly affects the dynamics of the hydration shell [ 46 ].…”

Synthesis of Nickel(II) Complexes of Novel Naphthalimide Based Heterodipodal Schiff Base Ligands, Structure, Characterization and Application for Degradation of Pesticides

“…[7a], Therefore, monitoring the acetylcholinesterase activity is an important factor to identify the efficiency of metal catalyst to hydrolyze the OPs. AchE hydrolyze the acetylcholine into thiocholine which is thiol‐containing reactive species . Free thiol group easily reduce the disulfide linkage of dithiobisnitro‐benzoate also called Ellman reagent and gives a thiobisnitro‐benzoate .…”