Preprint Article Version 1 Preserved in Portico This version is not peer-reviewed

An Investigation of Three-finger Toxin – nAChR Interactions through Rosetta Protein Docking

Version 1 : Received: 11 August 2020 / Approved: 14 August 2020 / Online: 14 August 2020 (09:57:35 CEST)

A peer-reviewed article of this Preprint also exists.

Gulsevin, A.; Meiler, J. An Investigation of Three-Finger Toxin—nAChR Interactions through Rosetta Protein Docking. Toxins 2020, 12, 598. Gulsevin, A.; Meiler, J. An Investigation of Three-Finger Toxin—nAChR Interactions through Rosetta Protein Docking. Toxins 2020, 12, 598.

Journal reference: Toxins 2020, 12, 598
DOI: 10.3390/toxins12090598

Abstract

Three finger toxins (3FTX) are a group of peptides that affect multiple receptor types. One group of proteins affected by 3FTX are nicotinic acetylcholine receptors (nAChR). Structural information on how neurotoxins interact with nAChR is limited and are confined to a small group of neurotoxins. Therefore, in silico methods are valuable in understanding the interactions between 3FTX and different nAChR subtypes, but there are no established protocols to model 3FTX – nAChR interactions. We developed a homology modeling and protein docking protocol to address this issue and tested its success on three different systems. First, neurotoxin peptides co-crystallized with acetylcholine binding protein (AChBP) were re-docked to assess whether Rosetta protein – protein docking can reproduce the native poses. Second, experimental data on peptide binding to AChBP was used to test whether the docking protocol can qualitatively distinguish AChBP-binders from non-binders. Finally, we docked eight peptides with known α7 and muscle-type nAChR binding properties to test whether the protocol can explain the differential activities of the peptides at the two receptor subtypes. Overall, our docking protocol succeeded in predicting both qualitative and specific aspects of 3FTX binding to nAChR and shed light on some unknown aspects of 3FTX binding to different receptor subtypes.

Subject Areas

nicotinic acetylcholine receptors; three-finger toxins; acetylcholine binding protein; protein – protein docking; computational modeling

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