Examining Binding Potential of Foldamers and Macrocycle Oligomers with Sugars
Taylor Bryan, Samatha Horowitz, Daniel P. Miller PhD
Department of Chemistry, Hofstra University, Hempstead, New York 11549
Introduction Results
The study investigates host-guest chemistry, focusing on the design of oligomeric foldamers with hydrophobic exteriors and electronegative cavities formed by inward-pointing carbonyl oxygens. These cavities enable selective binding of positively charged molecules, such as sugars, through noncovalent interactions like hydrogen bonding. The foldamers are designed with alternating amide and carbonyl groups in a spring-like structure, terminating with a tert-butyl tail. The research explores sugar transportation, critical for processes like glucose homeostasis, hormonal regulation, andATP production via glycolysis. While linear sugar forms are easier to transport, the study emphasizes challenges associated with bulkier ringstructured sugars, which are prevalent in biological systems. For instance, five-membered fructose rings were examined due to their equilibrium with six-membered forms, which resemble glucose in behavior. The study builds on previous findings where macrocycle hosts transported chloride ions, hinting at therapeutic potential for cystic fibrosis. This research extends the concept to sugar transport, emphasizing its biological importance and the adaptability of foldamers in various molecular environments.
Abbreviations to note: For the foldamers, 8 unit repeating oligomer residue (8mer), 12 unit repeating oligomer residue (12mer), and 16 unit repeating oligomer reside (16mer). For the macrocycles, single macrocycle (SM), double macrocycle (DMC) single chair (SC), single wheel (SW), and single bowl (SB).
Interestingly, Glucose was the only sugar that consistently became more stable when inserted into a foldamer host, as depicted by its negative SDE for all three foldamers. However, glucose's SDE is a positive value when placed inside a macrocycle.
Discussion
The dipole moment increases as the host size increases for all sugars, with the exception of lactose, mannitol, fructose, and maltose. Interestingly, the 12mer exhibits the highest dipole moment for these four sugars. Regarding the macrocycles, this direct relationship between host size and dipole moment was only followed for galactose, mannitol, and lactose. The single macrocycle experiences the greater dipole moment for all other sugar guests. The presence of the dipoles supports particular sugar placement in the cavity to fit the dipole vector.Another unique feature of the macrocycle is that it has the ability to shift from a bowl to chair form to accommodate a guest. When this occurs, the dipole is lost. Pore size was seen to increase with foldamer size with certain sugars. For the disaccharides, two patterns were found: For lactose and sucrose, the 8mer has the smallest pore, while the 12mer is the largest. However, for trehalose and maltose, the 12mer has the smallest pore size, whereas the 8mer is the largest. It is likely that this is due to trehalose and maltose having the two largest sugar volumes, causing the ranking of pore size to be rearranged. When considering the monosaccharides, galactose, mannitol, and sorbitol all experienced the 16mer having the largest pore size, with the 8mer being the smallest for galactose and sorbitol. Glucose followed the same trend as maltose and trehalose, as the 8mer has the largest pore sizing.
Conclusion
The study highlights that foldamers are highly effective in binding and transporting monosaccharides and disaccharides due to their flexible and larger cavities, which provide favorable interactions. Negative interaction energies across all tested sugars confirmed stable binding within the foldamer cavities. In contrast, macrocycles showed lower efficiency due to their smaller, more rigid pores.
Figure 2. (a) Table and picture of data for glucose. (b) Table and picture of data for sorbitol. (c) Table and picture of data for trehalose. (d) Table and picture of data for Maltose.
*Photo depicts the top view (left) and side view (right) of the 12mer host that depicts the dipole across the foldamer channel. All energies are in kcal/mol.
Smaller foldamers were better at transporting monosaccharides, while larger ones were more suited for disaccharides. As the foldamer size increased, the dipole moment and transport efficiency also improved. These findings suggest that foldamers could serve as therapeutic tools for targeted sugar transport, such as delivering glucose to energy-deficient areas or removing harmful sugars like D-galactose from the brain, which may otherwise contribute to premature aging.
References andAcknowledgements
Thank Dr. Gong and Dr. Zhong for helpful scientific discussions surrounding this project scope.
Figure 1 (a) Top, side, and electrostatic potential profile of 8mer foldamer with dipole moment.
(b) Top, side, and electrostatic potential profile of 16mer foldamer with dipole moment.