In a new study in JACS, we’ve taken a significant step toward expanding the diversity of polypeptide structures beyond what is found in nature. By systematically exploring over 200,000 combinations of 130 chemically diverse amino acids, we found several new repeating structures that exhibit unique low-energy conformations, opening up new possibilities for molecular engineering.

This research was led by recent Baker Lab graduate student Adam Moyer and Theresa Ramelot, a senior research scientist in the Montelione Lab at Rensselaer Polytechnic Institute. Collaborators included Oklahoma State University and the Barcelona Institute of Science and Technology in Spain. Scientists from the IPD’s Core R&D Labs helped generate high-resolution crystal structures.

Beyond the common alpha helix

Most proteins on Earth contain regular substructures like the alpha helix and beta sheet, which are stabilized by predictable patterns of hydrogen bonding. However, by incorporating non-biological amino acids, it’s possible to discover entirely new structural motifs that aren’t found in nature. Our study leverages the increased chemical diversity of noncanonical amino acids to systematically search for repeating peptide structures with stable, low-energy conformations. These novel secondary structures may serve as building blocks for novel peptides, proteins, and other types of designer molecules with medicinal or industrially useful properties.

A systematic approach to discovery

To find new secondary structures, we developed a computational pipeline that evaluates the stability of specific amino acid pairs then extends them into helical repeats. Using advanced energy evaluation techniques, including the AIMNet neural network, we were able to efficiently navigate a vast space of possible polypeptide configurations. From this, we selected ten promising candidates for experimental validation.

Experimental validation

We synthesized several polypeptides and characterized them using circular dichroism spectroscopy, NMR, and X-ray crystallography. Two of the polymers closely matched their computational models, confirming the effectiveness of our approach. These new structures provide fresh building blocks for molecular engineering, with potential applications ranging from drug delivery to materials science.

Implications and future directions

Our work demonstrates the potential of systematically exploring noncanonical amino acids to design novel polypeptide structures with enhanced stability and functionality, as exemplified by our lab’s recent Science paper on expansive cyclic peptide design. This approach, with its broad applicability, could lead to breakthroughs in biotechnology, such as creating drugs more resistant to degradation and polypeptide scaffolds capable of performing entirely new tasks.

Stay tuned as we continue to explore the untapped potential of complex molecules not seen in nature.

Funding

This research was supported by several federal, private, and philanthropic organizations. All funding sources are listed in the manuscripts.