Aqueous ionic liquids influence the disulfide bond isoform equilibrium in conotoxin AuIB: a consequence of the Hofmeister effect?

Abstract

The appearance of several disulfide bond isoforms in multiple cysteine containing venom peptides poses a significant challenge in their synthesis and purification under laboratory conditions. Recent experiments suggest that careful tuning of solvent and temperature conditions can propel the disulfide bond isoform equilibrium in favor of the most potent, native form. Certain aqueous ionic liquids (ILs) have proven significantly useful as solvents for this purpose, while exceptions have also been noted. To elucidate the molecular level origin behind such a preference, we report a detailed explicit solvent replica exchange molecular dynamics study of a conotoxin, AuIB, in pure water and four different aqueous IL solutions (~45-60% v/v). The ILs studied here are comprised of cations like 1-ethyl-3-methyl-imidazolium (Im) or 1-butyl-3-methyl-imidazolium (Im) coupled with either acetate (OAc) or chloride (Cl) as the counter anion. Our simulations unfold interesting features of the conformational spaces sampled by the peptide and its solvation in pure water and aqueous IL solutions. Detailed investigation into populations of the globular disulfide bond isoform of AuIB in aqueous IL solutions reveal distinct trends which might be related to the Hofmeister effect of the cation and anion of the IL and of specific interactions of the aqueous IL solutions with the peptide. In accordance with experimental observations, the aqueous [Im][OAc] solution is found to promote the highest globular isoform population in AuIB.

Simulation of differential structure and dynamics of disulfide bond isoforms of conopeptideAuIBin presence of humanα3β4nAChR

“…The present report is a continuation of a series of our works with conotoxin AuIB in the all atom level. [ 40,45,72 ] That is the reason why the receptor modeling and simulation in presence of the peptide is also done the same atomistic resolution. Although, it is implicit that accurate peptide‐receptor non‐bonding energies and the perturbation to the peptide structure by the receptor side chain motions could not be captured fully in this study as position restraints for the receptor are in place, nevertheless, the current study gives an overall idea of what differences a pair of isoform may experience in terms of structure and especially dynamics, when placed near such a binding site.…”

Inferring pathways of oxidative folding from pre-folding free energy landscapes of disulfide-rich toxins

“…1 for an overview), we use five µ-conotoxins as a relevant testing ground to explore whether the free energy landscape of short, disulfide-rich peptides lying closer to the hirudin end of the folding continuum will be significantly more rugged in the absence of disulfide bonds than will the free energy landscape of those that lie closer to the BPTI end. We perform replica exchange molecular dynamics (REMD) with the disulfide bonds disconnected, as has been previously done in the case of several α conotoxins [22][23][24] to study the effects of solvation in aqueous ionic liquids but not for the purpose of assessing prefolding equilibrium. By employing the diffusion map dimensionality reduction technique [25][26][27] in its composite formulation, 28 we are able to directly compare the energy landscapes of the different conotoxins in what is essentially a "shared basis" of the underlying lowerdimensional nonlinear manifold of the configurational space.…”

Snails In Silico: A Review of Computational Studies on the Conopeptides

“…Finally, Sajeevan and Roy performed MD simulations of α-AuIB and α-GI with disconnected disulfide bonds in water and water-ionic-liquid. They showed that the different solvents controlled the conformational landscape of the studied toxins, thus demonstrating that different ensembles of different isomers are thermodynamically favorable under different solvent conditions, potentially providing a route for thermodynamic control of in vitro folding [159,160].…”