Molecular Modeling of Folding and Preferred Regioisomer Formation in α-Conotoxins

Abstract

Conotoxins are short peptides that are isolated from predatory marine cone snail venom. They are unique from other peptides in that they have the ability to differentiate between various types of ion channels and this makes them ideal diagnostic tools in the characterization of neuronal pathways and in drug development. The subject of our study, α- conotoxins, are 13 to 15-amino acid peptides containing 4 cysteine residues. Thus, three possible regioisomers can form via disulfide bond formation upon synthesis of these compounds. We report a method to model the conformational folding of α-conotoxins and the factors that affect the synthesis of specific regioisomers. We use a combination of molecular dynamics methods to determine the geometric factors (S-S distance, for instance) and ab initio methods to determine the conformational energy and molecular orbital information. Experimental work by the Hargittai group has determined that the nature of the amino acid at the 9 position strongly directs the formation of a specific regioisomer. Our model agrees with experimental observations that identify the role of the amino acid proline in directing the proper folding of α-conotoxins. We have observed that the presence of proline (1) directs the folding towards the proper (native) sulfur-sulfur pairs, and (2) allows less flexibility in the folding. The molecular orbital methodology has also provided insight into the directionality and energetics of the disulfide bond formation.