Investigation of α-conotoxin unbinding using umbrella sampling

Bioorganic & Medicinal Chemistry Letters
Rilei YuTao Jiang

Abstract

α-Conotoxins, a class of short and disulfide rich peptide toxins, specifically and potently block nicotinic acetylcholine receptors (nAChRs). In this study umbrella sampling was performed to study the unbinding pathways and potential of mean force (PMF) of α-conotoxin ImI and PNIA(A10L,D14K). Our results suggest that (i) the unbinding pathways of ImI and PNIA(A10L,D14K) are similar despite of their different disulfide framework and structure, and (ii) α-conotoxin unbinding requires large conformation perturbation of the C-loop and the backbone flexibility of the C-loop can affect the binding or unbinding kinetics of the α-conotoxins. In addition, (iii) umbrella sampling gave correct ranking of the binding affinities of ImI and PNIA(A10L,D14K) indicating its efficacy on prediction of the binding affinities of α-conotoxins and implicating its potential application in design of more potent α-conotoxin analogs.

References

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Oct 8, 2005·Journal of Computational Chemistry·David Van Der SpoelHerman J C Berendsen
Feb 14, 2007·ChemMedChem·M Novella RomanelliFulvio Gualtieri

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Citations

Apr 1, 2017·Future Medicinal Chemistry·Giuseppe Deganutti, Stefano Moro
Jul 15, 2017·Proteins·Argha NandyLeif A Eriksson
Jun 27, 2019·Marine Drugs·Harry Morales DuqueOctávio Luiz Franco
Mar 6, 2019·Marine Drugs·Rachael A MansbachS Gnanakaran

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