Structural and biophysical studies of biomimetic poly-N-substituted glycine oligomers: Intermolecular and intramolecular peptoid interactions in solution

Several classes of peptidomimetics are being studied towards the discovery of functional synthetic mimics of natural peptide structure and function. Here, we examine the solution behavior of poly-N-substituted glycine oligomers (peptoids). In our group, peptoids are studied for applications in medicine and material science, and fundamental studies of the intramolecular and intermolecular behavior of peptoids in solution are still incomplete. Contrary to published results, we have discovered that peptoids with at least two-thirds alpha-chiral aromatic residues can self-assemble in solution to form dimers and higher ordered structures through aromatic interactions.;A library of peptoids was synthesized and analyzed using CD and UV spectroscopy, and equilibrium analytical ultracentrifugation. Our library consisted of sequence motifs of interest in the development of potent and selective, peptoid-based antimicrobial peptide mimics, or ampetoids, to determine the role of peptoid-peptoid interactions in ampetoid mechanism of action. We found that peptoids that self-assemble were more potent due to a higher local concentration of peptoid at the bacterial membrane. Another library of peptoids developed as mimics of SP-B protein for the treatment of neonatal respiratory distress and acute respiratory distress syndromes, was analyzed to determine the role of peptoid assemblies in a peptoid-based lung surfactant formulation. We support the hypothesis that peptoids that self-assemble more closely mimic the structure and function of natural SP-B protein, and showed improved results over monomeric peptoids. Analysis of disulfide bonded peptoid dimers did not yield improved results in vitro.;The importance of high resolution peptoid structures cannot be neglected. Structures reported in literature and their circular dichroism spectra are in conflict. Though peptoids form polyproline helices, CD spectra of peptoids with aromatic side chains are reminiscent of alpha-helices. We attribute the unexpected CD spectrum to peptoid assemblies rather than individual helices. Using existing structural data and computational techniques, we found that the predicted CD spectra would be that of a polyproline helix.;We designed a library of peptoids with high sequence diversity adhering to motifs reported to form stable helices. Several of the compounds were synthesized, and diagnostic CD and NMR spectra were recorded to determine the possibility of solving a structure.