Career: development and application of novel methods for rapid, facile chemical protein synthesis

The National Science Foundation Division of Chemical, Bioengineering, Environmental, and Transport Systems awarded Hampden-Sydney College $542,746 on August 1, 2026, under the Engineering program (CFDA 47.041) to develop folding-assisted ligation, a novel method for rapid chemical protein synthesis.

The recipient will develop techniques to synthesize proteins through folding-assisted ligation, which harnesses proteins' intrinsic self-assembly ability to facilitate production without requiring cysteine at the ligation site—a constraint of traditional native chemical ligation. The project will apply these methods to synthesize immunoglobulin domain-containing proteins, mirror image proteins for use in chemical biology and racemic crystallography, and the Fc domain of antibodies to enable investigation of glycosylation-dependent functionality. Computer modeling of protein structure will be coupled with experimental work to drive technique development. The award supports development of education modules and a research-based international study abroad program for undergraduate STEM majors, intended to develop the workforce needed for biomanufacturing.

Work is performed in Farmville, Virginia, with a period of performance from August 1, 2026, through July 31, 2031. This is a Project Grant, assistance type under the NSF Engineering directorate.

Abstract

Efforts to develop protein therapeutics are hampered by an inability to produce the proteins exactly as they are found in humans. Protein folding is often critical to the function and activity of proteins. Chemical synthesis can be used to assemble the amino acid sequences found in natural proteins. IT can't guarantee the proteins would be correctly folded. This career project involves developing a new approach to the folding problem. The technique is called folding-assisted ligation. The approach harnesses proteins? Intrinsic ability to self-assemble to facilitate their rapid production. Computer modeling of protein structure will be coupled with experiments to drive the development of this technique. Education modules will be developed. A research-based international study abroad program for undergraduate stem majors will be developed. These will help develop the workforce needed to power biomanufacturing. Chemical protein synthesis enables site-specific functionalization. The objective of this project is to develop folding-assisted ligation, a strategy for the total chemical synthesis of proteins. Unlike traditional native chemical ligation, which requires cysteine at the ligation site, the proposed method could drive ligation at any amino acid in a process driven by folding-induced proximity. The proposed project will (1) develop folding-assisted ligation techniques for immunoglobulin domain-containing proteins, (2) apply these methods to synthesize mirror image proteins for use in chemical biology and racemic crystallography, and (3) chemically synthesize the FC domain of antibodies to enable the investigation of glycosylation-dependent functionality. This approach combines computational structural prediction tools, self-assembly of peptide fragments, and chemical synthesis in a novel conceptual framework. Successful development of folding-assisted ligation would provide a general, broadly accessible platform for the synthesis of large and complex proteins with custom modifications. The long-term goal is to create broadly accessible tools to empower researchers across disciplines to access chemically defined proteins for structural biology, therapeutic development, and protein engineering. This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the foundation's intellectual merit and broader impacts review criteria.- subawards are not planned for this award.