Molecular Flasks
Reflecting recent work in the Woolfson and Oliver Labs
Dek Woolfson is a 2025 APS duVigneaud Award Winner
To address the formidable challenge of binding and orienting multiple small molecules for directed chemical reactions, researchers in the Woolfson and Oliver groups at the University of Bristol, research in the Woolfson and Oliver labs at Bristol University, led by graduate student Rokas Petrenas, pictured at right, as publishedpublished in the Journal of the American Chemical Society, present an innovative approach centered on de novo designed α-helical barrel, αHB, peptide assemblies. These assemblies, composed of five or more α-helices arranged to form solvent-accessible central channels, act as biomimetic "molecular flasks." Their internal dimensions and chemistries can be precisely tuned, mirroring strategies often employed in supramolecular, polymer, and materials chemistry.
The Thomas Oliver Group at the University of Bristol
The study highlights two pivotal applications of these functional assemblies. First, using Förster resonance energy transfer, FRET, as a readout, the researchers demonstrate that specific αHBs can encapsulate two organic dyes—1,6-diphenyl-1,3,5-hexatriene, DPH, and Nile red—within their channels, enabling highly efficient energy transfer on the picosecond timescale. Second, the αHBs facilitate the photodimerization of anthracene molecules, showcasing their ability to organize reactants within confined environments to promote specific chemical transformations. Importantly, the outcomes of these experiments depended on the precise selection and design of αHB structures, as not all configurations were equally productive, underscoring the importance of structural tuning.
The authors emphasize that these αHB peptide assemblies replicate key enzyme-like functionalities, including selective ligand binding and the promotion of reactive conformations, through the interplay of shape complementarity and hydrophobic interactions within their lumens—features typically achieved through complex active sites in natural enzymes. Moreover, the versatility of these αHBs extends far beyond the presented applications. Their thermostability, tolerance for mutations –including polar, charged, and noncanonical amino acids), and adaptability via computational protein design and directed evolution position them as promising tools for catalysis in aqueous environments.
By leveraging the rational predictability of molecular flask-like designs, this work offers a platform for creating modular, robust, and highly customizable scaffolds for small-molecule binding and catalysis. It paves the way for advances in chemical synthesis, biotechnology, and materials science, further bridging the gap between engineered peptide assemblies and enzyme-like catalytic systems.