Several analgesic α-conotoxins have been isolated from marine cone snails. Structural modification of native peptides has provided potent and selective analogues for two of its known biological targets—nicotinic acetylcholine and γ-aminobutyric acid (GABA) G protein-coupled (GABAB) receptors. Both of these molecular targets are implicated in pain pathways. Despite their small size, an incomplete understanding of the structure-activity relationship of α-conotoxins at each of these targets has hampered the development of therapeutic leads. This review scrutinises the N-terminal domain of the α-conotoxin family of peptides, a region defined by an invariant disulfide bridge, a turn-inducing proline residue and multiple polar sidechain residues, and focusses on structural features that provide analgesia through inhibition of high-voltage-activated Ca2+ channels. Elucidating the bioactive conformation of this region of these peptides may hold the key to discovering potent drugs for the unmet management of debilitating chronic pain associated with a wide range of medical conditions.

We investigate the perchlorate anion, ClO, microhydrated with up to eight water molecules using infrared photodissociation (IRPD) spectroscopy aided by density functional theory computations. The features observed in the IRPD spectra of D-tagged ClO(HO) with n = 0-8 in the O-H stretching (2800-3800 cm) and fingerprint (800-1800 cm) spectral ranges are assigned to vibrational modes of the solvent, i.e., free and hydrogen-bonded O-H stretching and HO bending modes, and of the solute, i.e., perchlorate stretching modes. The splitting of the triply degenerate antisymmetric stretching mode in the bare ClO (1102 cm) upon microhydration directly reports on the symmetry of the local solvation network, while the red-shift of the hydrogen-bonded O-H stretching bands in comparison to those of free O-H oscillators (>3700 cm) reflects the strength of the anion-water (3550-3650 cm) and water-water (3240-3540 cm) hydrogen bonds. The stronger water-water interaction leads to an early onset of water-water hydrogen bond formation (n = 2) and eventually asymmetric solvation of ClO, evidenced by the population of the second and third hydration shells at n = 5 and n = 8, respectively, before the first hydration shell is completed. The present study provides a bottom-up view of the initial stages of hydrogen-bond network formation around a high surface propensity anion, and these insights are discussed in the context of recent results obtained for the water-vapor interface of perchlorate solutions.