Enumerative\nDiscovery of Noncanonical\nPolypeptide Secondary Structures

Energetically favorable\nlocal interactions can overcome the entropic\ncost of chain ordering and cause otherwise flexible polymers to adopt\nregularly repeating backbone conformations. A prominent example is\nthe α helix present in many protein structures, which is stabilized\nby <i>i</i>, <i>i</i> + 4 hydrogen bonds between\nbackbone peptide units. With the increased chemical diversity offered\nby unnatural amino acids and backbones, it has been possible to identify\nregularly repeating structures not present in proteins, but to date,\nthere has been no systematic approach for identifying new polymers\nlikely to have such structures despite their considerable potential\nfor molecular engineering. Here we describe a systematic approach\nto search through dipeptide combinations of 130 chemically diverse\namino acids to identify those predicted to populate unique low-energy\nstates. We characterize ten newly identified dipeptide repeating structures\nusing circular dichroism spectroscopy and comparison with calculated\nspectra. NMR and X-ray crystallographic structures of two of these\ndipeptide-repeat polymers are similar to the computational models.\nOur approach is readily generalizable to identify low-energy repeating\nstructures for a wide variety of polymers, and our ordered dipeptide\nrepeats provide new building blocks for molecular engineering.