Chemical systems found in biology are vastly more complex than what we can currently design. This is possible because of the structural complexity of biological macromolecules (large molecules), especially proteins. This complexity is achieved through molecular folding, where a polymer, a long chain-like molecule, is folded into a specific shape. Put another way, control over molecular structure through folding makes it possible for biology to achieve sophisticated function in networks of chemical reactions.

Our ability to engineer non-biological molecules that fold by analogy with proteins, called "foldamers", is still very limited. This is an important goal, however, as achieving increased structural sophistication would enable new systems for molecular recognition and catalysts that operate under similar principles to those from biology but under very different conditions or directed at different aims. The overall goal of this project is to study molecular folding, particularly with respect to controlling foldamer dynamics and the construction of complex folded molecular architectures. The focus is on a class of foldamers called ortho-phenylenes. They are structurally very simple and quite different from biological molecules, consisting of a simple chain of benzene rings. Nevertheless, they spontaneously fold into helical geometries in solution, driven by attractive interactions between every third ring. The o-phenylenes have some important features that make them an excellent platform for studying folding: their folding is dynamic because the stabilizing interactions are not very strong, their folding propensity can be controlled, and their three-dimensional structures can be determined in detail using Nuclear Magnetic Resonance (NMR) spectroscopy.

Key results from this project include: (1) We developed a method to use strategically placed fluorine atoms to get richer and more-easily interpreted information about o-phenylene structure in solution using NMR spectroscopy. This technique allows us to analyze the folding of ever more-complicated systems. (2) We showed that folding could be combined with methods of molecular self-assembly to construct macrocycles (large rings) containing multiple o-phenylene units. Importantly, we showed that the assembly process was controlled by how well the o-phenylenes fold: if they fold well, the structure of the product must accommodate this by forming larger rings, whereas if they fold weakly they will misfold in predictable ways to allow smaller rings to form. (3) We demonstrated that the geometry of an o-phenylene foldamer can be controlled by attaching appropriate groups to either its ends or its middle. This allows us to, for example, control whether the oligomer folds into a left- or right-handed helix. Other accomplishments from this grant include using host–guest chemistry to control the folding of a short o-phenylene and incorporating o-phenylene helices into polymer materials as molecular springs.

Broader impacts from this work include the development of a teaching laboratory activity where undergraduate students explore how chemical "fuels", analogous to ATP in biology, can be used to effect temporary assembly of molecular components. Members of the research group also participated in Miami University's Louis Stokes Alliance for Minority Participation program and outreach efforts.

Last Modified: 11/28/2023
Modified by: Christopher S Hartley