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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 is 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 followed 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, the docking protocol predicted the qualitative and some specific aspects of 3FTX binding to nAChR with reasonable success and shed light on unknown aspects of 3FTX binding to different receptor subtypes.
Highlights
The peptides bound to acetylcholine binding protein (AChBP) and homolog structures covered α-bungarotoxin, α-cobratoxin, and α-conotoxin derivatives PnIA, ImI, TxIA (A10L), BuIA, GIC, PeIA, LsIA, LvIA (Table 1). α-conotoxin derivatives have different structures compared to 3FTX proteins limiting their usability as a benchmark
The second purpose of the α-conotoxin docking calculations is to see whether the protocol is capable of sampling the conformational changes associated with peptide binding. nicotinic acetylcholine receptors (nAChR) have flexible C- and F-loops that may go through large structural changes upon ligand binding, and the cross-docking calculations address whether the ensemble docking protocol we chose is able to reflect these structural changes
We looked at the fraction of native contacts conserved (Fnat) to determine whether the sidechain contacts predicted by Rosetta are consistent with the native contacts
Summary
Nicotinic Acetylcholine Receptors (nAChR) Play Important Roles. Nicotinic acetylcholine receptors (nAChR) are pentameric ligand-gated ion channels belonging to the Cys-loop receptor superfamily. NAChR play important roles in neuromuscular transmission, addiction, nociception, and cognition [1]. The traditional ligand binding site of nAChR is called the orthosteric site. This site is characterized by a number of aromatic residues that form an “aromatic cage”. Ligands bind to that cage through cation–π and hydrophobic interactions [2,3]. Heteromeric nAChR such as the muscle-type and α4β2 nAChR have two orthosteric binding sites formed by α and non-α subunits [4], whereas homomeric nAChR such as α7 and α9 nAChR have five putative binding sites at the α-α interfaces [5]
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