Molecular simulation study of the unbinding of α-conotoxin [ϒ4E]GID at the α7 and α4β2 neuronal nicotinic acetylcholine receptors

Discovery of peptide ligands through docking and virtual screening at nicotinic acetylcholine receptor homology models

“…This result agrees with the recent α-GID modeling study of Suresh and Hung (15). Using sophisticated umbrella sampling and free-energy calculations, they came to the conclusion that a point mutation on the N-terminal tail, a different region of α-GID than the one we focused on, could potentially also impart specificity for the α4β2 nAChR (15). More generally, our findings are in accord with published results of Hogg et al (55) and Luo et al (56), who showed that a single-residue alteration in a similar conotoxin, α-PnIA, is sufficient for switching its nAChR subtype selectivity.…”

“…These findings suggest that even a relatively modest virtual screen of 256 α-GID point mutants, further focused by the use of postdocking filters, can uncover novel peptide ligands with favorable properties. This result agrees with the recent α-GID modeling study of Suresh and Hung (15). Using sophisticated umbrella sampling and free-energy calculations, they came to the conclusion that a point mutation on the N-terminal tail, a different region of α-GID than the one we focused on, could potentially also impart specificity for the α4β2 nAChR (15).…”

“…The receptor is formed from five homologous subunits, consisting of either two α4 subunits and three β2 subunits or three α4 subunits and two β2 subunits, organized like barrel staves to form a central channel (14). Cations flow through the channel when acetylcholine (ACh) is bound at specific interfaces between subunits in the extracellular domain (14), where α-GID presumably binds competitively (9,15). In addition to the α4β2 nAChR, α-GID potently antagonizes the rat α3β2 nAChR (IC 50 reported as 3.1-3.4 nM and 36 nM) as well as the rat α7 nAChR (IC 50 = 4.5-5.1 nM) (9)(10)(11).…”

“…In addition to the α4β2 nAChR, α-GID potently antagonizes the rat α3β2 nAChR (IC 50 reported as 3.1-3.4 nM and 36 nM) as well as the rat α7 nAChR (IC 50 = 4.5-5.1 nM) (9)(10)(11). Consequently, there has been significant interest in engineering an analog of α-GID that antagonizes the α4β2 nAChR but not the α3β2 and α7 nAChRs, especially for the human nAChRs (9)(10)(11)15). A recent study by Banerjee et al (9) used structure-guided mutagenesis to discover…”

Modelling the interactions between animal venom peptides and membrane proteins

“…A more accurate but computationally intensive method to compute the potential of mean force is umbrella sampling, in which several simulations are carried out with the ligand restrained at different distances from the initial binding site (Woo and Roux, 2005). This approach has been used to study the unbinding of ImI and PnIA from AChBP (Yu et al, 2016) as well as GID unbinding from α4β2 and α7 nAChRs (Suresh and Hung, 2016). The increased computational power only recently enabled such tedious computations because the conformational landscape of the relative flexible C-loop needs to be modelled during the unbinding process from this large receptor.…”