Positive cooperative regulation of double binding sites for human acetylcholinesterase

Abstract

Acetylcholinesterase is a potent enzyme that regulates neurotransmission by rapidly hydrolyzing the neurotransmitter acetylcholine in synapses of the nervous system. As drug target of anti-AD, it has catalytic and peripheral anionic sites. However, the regulation relation between these two sites is unclear. Therefore, we constructed dynamics fluctuation network based on all-atom molecular dynamics simulations to reveal the regulation mechanism. The results suggest that the correlation network in double-site system (hAChE/TZ5) is distinctly different from that in the free state and single-site systems (hAChE/huprine and hAChE/1YL). The community network analysis indicates that the information freely transfers from the peripheral anionic site to the catalytic active site in hAChE/TZ5. Furthermore, the binding free energy between the inhibitor and hAChE for hAChE/TZ5 is significantly lower than of either hAChE/huprine or hAChE/1YL. Thus, a hypothesis of 'positive cooperative regulation' is proposed for the regulation of double binding sites and further confirmed by the weakening and mutation community analyses. Finally, one possible cooperative regulation pathway of W86-TZ5-W286 was identified based on the shortest path algorithm and was confirmed by the network perturbation analysis. Interestingly, the regulation pathway for single-site systems is significantly different from that of dual-site system. The process targeting on the shortest pathway can better regulate the hydrolyzing the neurotransmitter acetylcholine and significantly inhibit the aggregation of Aβ amyloid.

Creatinase: Using Increased Entropy to Improve the Activity and Thermostability

“…The structure with the highest number of neighbors was chosen as the cluster’s center, and formed a cluster with all its neighbors . The interactions within protein residues were calculated using in-house software . The hydrogen bond was defined when the distance between two polar heavy atoms either of which has a hydrogen atom is less than 3.5 Å and the angle of these three atoms is larger than 120°.…”

Identification of hACE2-interacting sites in SARS-CoV-2 spike receptor binding domain for antiviral drugs screening

“…RMSDs and root mean square fluctuations (RMSFs) of Cα were analyzed with the CPPTRAJ program in AmberTools18 ( Case et al, 2018 , Song et al, 2017 ). The MMPBSA in AmberTools18 ( Case et al, 2018 ) was used to create a compatible complex, to generate SARS-CoV-2 spike RBD and hACE2 topology files from a solvated topology file, and to calculate the total binding free energy of SARS-CoV-2 spike RBD and hACE2 ( Liu et al, 2017 ). The calculation was based on the simulation from 50 ns to 150 ns.…”

Catalytic mechanism of butane anaerobic oxidation for alkyl‐coenzyme M reductase

“…This method was used to reveal the information transfer for other biomolecule systems. (Liu et al., 2017; Rahman et al., 2016; Wang et al., 2016; Yang et al., 2016; Ye et al., 2017; Zhang, Jiang, et al., 2016; Zhang, Luo, et al., 2016).…”