De novo Design of Peptide Folds of Stereochemically Rationalized Molecular Architecture

摘要

Nature extracts phenomenal purchase from an alphabet of stereochemically frozen composition. The bonanza could be extended by artificially restoring the molecular alphabet to stereochemical parity. The homochiral nature of polypeptide stereochemical structure restricts the choice of both residue and motif level conformation in proteins to a handful and therefore the possibility for tertiary structure to approx = 10~3 topologically distinct folds. Recruitment of stereochemistry as an additional, higher level, sequence variable promises to multiply the conformational template in polypeptide structure towards de novo design, with added bonus that molecular morphologies could be customized stereochemically, by stereospecific folding of polypeptides of heterochiral structure. Illustrating this excursion with Nature's design algorithm, beyond constrains of homochiral alphabet, 14 to 20-residue peptides were recently shown to adopt "bracelet" and "boat" shaped molecular morphologies, along with protein like ordering of conformation. Another variant is now achieved as a "canoe" shaped molecule or as a gramicidin-A channel as if sliced into half. An artificial construct, the "nanotube" was made from building blocks that could be imagined as slabs of gramicidin "channel" sliced horizontally. Performing imaginary longitudinal bisection on gramicidin "channel", we designed molecular "canoe" and our results suggest that indeed a "canoe" type molecular fold exists in water with a double-headed "catgrip" like structure, as observed in proteins. With the lifting of stereochemical degeneracy in Nature's building block alphabet, it may be possible to bridge the gulf between what is possible biologically and what has been accomplished artificially.