Temperature‐dependent molecular dynamics study reveals an ionic liquid induced 3₁₀‐ to α‐helical switch in a neurotoxin

Abstract

Thermal melting and recooling of AuIB, a neurotoxic conopeptide and a highly potent nonaddictive pain reliever is investigated thoroughly in water and an ionic liquid (IL) 1-butyl-3-methylimidazolium Chloride, [Im ][Cl] by classical molecular dynamics simulations. Structural evolution of AuIB in water and the IL is observed at different temperatures between 305 and 400 K, to explore how highly viscous ionic solvents affect the peptide structure as compared to conventional solvent water. At 305 K, unlike water, the coercive effect of IL frustrates AuIB secondary structural motifs significantly. As the temperature is raised, a very interesting IL induced conformational transition from 3 - to α-helix is noticed in the peptide, presumably triggered by a significant restructuring of the peptide H-bond network. The backbone length distributions of the peptide indicate that the IL induced conformational switching is accompanied by a reduction of the axial rise of the helical region, encompassing the residues Pro-6 to Ala-10. Further, we estimated the void space available to the peptide for its structural relaxation within the first solvation shell of ∼5 Å in water as well as in IL. A temperature increase by 100 K, opens up an estimated void volume of ∼70 Å , equivalent to the volume of approximately six water molecules, around the peptide in IL. Cooling simulations of AuIB point to the crucial interplay between thermodynamically favored AuIB conformers and their kinetic control. This study provides a comprehensive understanding of the ionic solvation of biomolecules reinforcing previous experimental findings.

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

“…It is a favorable target to study the differential binding pattern of the disulfide bond isoforms of a peptide toxin with its selective receptor (α 3 ) 3 -(β 4 ) 2 nAChR owing to the availability of several experimental and computational studies in the literature. [33][34][35][36][37][38]40,45,46,64,65] Figure 1 shows the NMR solution phase structures of the native globular and non-native ribbon isoforms of AuIB.…”

“…Some of the peptide-aqueous IL simulation data are included in this report for comparison purposes. [33,40,45] Figure 2 depicts the homology modeled structure of the pentameric (α 3 ) 3 -(β 4 ) 2 human nAChR along with the α 3 (+)β 4 (−)…”

“…Five random starting configurations, picked at every 2 ns led to production trajectories of 20 ns each, totaling to 0.1 μs. [33,45] 2.1. ).…”

“…[43,44] Previously, we have seen the differential effect of disulfide crosslinks on the structural and thermodynamical properties of two α-conotoxins, AuIB and GI, isolated respectively from Conus aulicus and Conus geographus. [33,40,45] The present report focuses on exploring how the subtle differences in disulfide linkage pattern of the native globular and non-native ribbon isoforms of AuIB lead to differential binding to the Cys-loop of a α 3 (+)β 4 (−) subunit junction of human (α 3 ) 3 -(β 4 ) 2 nAChR (the natural binding site of the globular isoform) as modeled following the work of Abraham et al [26] The results are compared to some of our previous works on AuIB, with both disulfide bonds kept intact and broken, in neat water, [33] neat 1-butyl-3-methyl-imidazolium chloride, [Im 41 ][Cl], [45] and 50% (vol/vol) aqueous 1-ethyl-3-methyl-imidazolium acetate, [Im 21 ][OAc]. [31,40] 2 | METHODOLOGY AND SIMULATION DETAILS…”

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

“…The AMBER all atom force field developed by Cornel et al, and modified in CHARMM format, has been used to describe the bonding and nonbonding potentials of AuIB (Cornell et al 1995). As mentioned in our previous works on AuIB (Roy and Lakshminarayanan 2016;Sajeevan 2017), this particular force field can parameterize the terminal as well as the non-terminal cysteine residues in AuIB, which may be either disulfidebonded or reduced. The water molecules are explicitly modeled by the TIP3P force field as incorporated in CHARMM (Jorgensen et al 1983;Jorgensen and Jenson 1998).…”