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  Kinetics of huperzine a dissociation from ccetylcholinesterase via multiple unbinding pathways.

Rydzewski, J., Jakubowski, R., Nowak, W., & Grubmüller, H. (2018). Kinetics of huperzine a dissociation from ccetylcholinesterase via multiple unbinding pathways. Journal of Chemical Theory and Computation, 14(6), 2843-2851. doi:10.1021/acs.jctc.8b00173.

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Item Permalink: http://hdl.handle.net/21.11116/0000-0001-3E5B-5 Version Permalink: http://hdl.handle.net/21.11116/0000-0001-7946-9
Genre: Journal Article

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Rydzewski, J.1, Author              
Jakubowski, R., Author
Nowak, W., Author
Grubmüller, H.1, Author              
Affiliations:
1Department of Theoretical and Computational Biophysics, MPI for biophysical chemistry, Max Planck Society, ou_578631              

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 Abstract: The dissociation of huperzine A (hupA) from Torpedo californica acetylcholinesterase (TcAChE) was investigated by 4-microsecond unbiased and biased all-atom molecular dynamics (MD) simulations in explicit solvent. We performed our study using memetic sampling (MS) for the determination of reaction pathways (RPs), metadynamics to calculate free energy, and maximum-likelihood estimation (MLE) to recover kinetic rates from unbiased MD simulations. Our simulations suggest that the dissociation of hupA occurs mainly via two RPs: a front-door along the axis of the active-site gorge (pwf) and through a new transient side-door (pws), i.e., formed by the Omega-loop (residues 67--94 of TcAChE). Analysis of the inhibitor unbinding along the RPs suggests that pws is opened transiently after hupA and the Omega-loop reach a low free-energy transition state characterized by the orientation of the pyridone group of the inhibitor directed toward the Omega-loop plane. Unlike pws, pwf does not require large structural changes of TcAChE to be accessible. The estimated free energies and rates agree well with available experimental data. The dissociation rates along the unbinding pathways are similar, suggesting that the dissociation of hupA along pws is likely to be relevant. This indicates that perturbations to hupA-TcAChE interactions could potentially induce pathway hopping. In summary, out results characterize the slow-onset inhibition of TcAChE by hupA, which may provide the structural and energetic basis for the rational design of the next-generation slow-onset inhibitors with optimized pharmacokinetic properties for the treatment of Alzheimer's disease.

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Language(s): eng - English
 Dates: 2018-05-012018-06-12
 Publication Status: Published in print
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 Rev. Method: Peer
 Identifiers: DOI: 10.1021/acs.jctc.8b00173.
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Title: Journal of Chemical Theory and Computation
Source Genre: Journal
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Pages: - Volume / Issue: 14 (6) Sequence Number: - Start / End Page: 2843 - 2851 Identifier: -