Relationship between excluded volume interactions and biological activity in D-leucine containing sequences

Conus snail are a group of predatory living in tropical oceans all over the word. They can produce highly diversified conotoxins for defense and predation. Conotoxins are believed to number about 50.000, and could serve as a rich source of active compounds. Conotoxins are mainly disulfide bond-rich peptides of 10-40 residues. A small number of conotoxins have zero or only one disulfide bond; they are classified in different families of D-residue containing conotoxins: contryphans, conophan and conomap. Apart contryphans (eight amino acids long with highly conserved sequence motifs) other gene products that have been characterized with D-amino acids are quite a heterogeneous assemblage. Despite this it has been noted that there are preferential loci for modification, i.e. either for the second amino acid from the N-terminus, or on the third amino acid from the C-terminus. Another striking feature of conotoxins is the high content of different post-translational modifications. Here we are interested to epimerization of different residues. DNA cloning has shown that at those positions where a D-amino acid is found in the end product, a normal codon for the corresponding L-amino acid is present. This implies that the D-residue are formed from L-amino acid by a post-translational reaction. Here we report about homologues sequences of the native peptide conotoxins having L-leucine on the third amino acid from the C-terminus and the isomer with D-leucine in the same position. Our work highlight the importance of structural factors, beyond the disulfide pattern and electrostatic interactions, in the understanding of the functional properties of bioactive peptides. The latter needs to be considered when designing analogues for further applications.