U.S. Department of Energy

Pacific Northwest National Laboratory

For a PNNL Team, a Science Hit

Computational design explores and illuminates cyclic peptides (macrocycles) across a vast energy landscape. Illustration by Vikram Mulligan, University of Washington

In the Dec. 15 issue of Science, the Biological Science Division's Yehia M. Ibrahim, Ian K. Webb, John R. Cort, and Joshua N. Adkins were among co-authors of a paper on computational strategies for designing peptide macrocycles that will spur new drug designs and other advances in technology.

The main authors were from the Institute for Protein Design and the Howard Hughes Medical Institute, both University of Washington (UW) entities.

Peptides are thought of as smaller than protein molecules, and also potentially different in structure and function. Technological uses, such as drug design, could benefit from the molecular stability of small cyclic peptides known as macrocycles, which may even be configured to have antibody-like selectivity.

Before the computational design work outlined in the Science paper, there was no way to systematically design peptide macrocycles with specific shapes and sizes. Present methods rely on random library selection, which is powerful but limited, and which leaves what the paper itself called "a vast sequence space" uncovered.

The new design strategies will spur the creation of ordered macrocycles that bind to molecular targets with precise shapes, and then allow candidate shapes to be stored in a digital library. This approach, the paper claims, will "vastly increase the available starting scaffolds for both rational drug design and library selection methods."

A SLIM Contribution

Also involved in the research was the Environmental Molecular Sciences Laboratory (EMSL), a U.S. Department of Energy Office of Science user facility located on the PNNL campus.

Adkins and the other contributors from the Lab used the Structures for Lossless Ion Manipulations (SLIM) technology developed at EMSL. (Richard D. Smith is principal investigator for SLIM development; Ibrahim, one of the Science paper's co-authors, is the SLIM co-inventor and developer.)

SLIM is used for very high throughput sample processing, for separations, and for other manipulations of ions in the gas phase—particularly in conjunction with mass spectrometry.

"We used the SLIM technology to evaluate the compactness of the synthesized molecular macrocycles," said Adkins, who directs PNNL's Integrative Omics Group. He said that supported "calculated behaviors" arrived at by the UW research group led by corresponding author David Baker.

Further Reading

December 2017
| Pacific Northwest National Laboratory