Synthesis and Solution-Phase Characterization of Sulfonated Oligothioetheramides

Abstract

Nature has long demonstrated the importance of chemical sequence to induce structure and tune physical interactions. Investigating macromolecular structure and dynamics is paramount to understand macromolecular binding and target recognition. To that end, we have synthesized and characterized flexible sulfonated oligothioetheramides (oligo-TEAs) by variable temperature pulse field gradient (PFG) NMR, double electron–electron resonance (DEER), and molecular dynamics (MD) simulations to capture their room temperature structure and dynamics in water. We have examined the contributions of synthetic length (2–12mer), pendant group charge, and backbone hydrophobicity. We observe significant entropic collapse, driven in part by backbone hydrophobicity. Analysis of individual monomer contributions revealed larger changes due to the backbone compared to pendant groups. We also observe screening of intramolecular electrostatic repulsions. Finally, we comment on the combination of DEER and PFG NMR measurements via Stokes–Einstein–Sutherland diffusion theory. Overall, this sensitive characterization holds promise to enable de novo development of macromolecular structure and sequence–structure–function relationships with flexible, but biologically functional macromolecules

Antibacterial isoamphipathic oligomers highlight the importance of multimeric lipid aggregation for antibacterial potency

“…Thus, they were ideal for exploring new parameters for sequence–structure–function optimization of membrane-disrupting antimicrobials. We confirmed similar solution-phase structures using small- and wide-angle X-ray scattering (SAXS/WAXS), as well as pulsed field gradient (PFG) nuclear magnetic resonance (NMR) and pulsed electron paramagnetic resonance (EPR) processed within the molecular Stokes–Einstein–Sutherland (SES) relation 40 . However, directed by differences in biophysical observations, we explored the interaction of these oligomers with supported bacterial mimetic bilayers using fluorescence microscopy, fluorescence recovery after photobleaching (FRAP), and oligomer–lipid extraction.…”

“…This calculation uses the slope of the plot of diffusion vs. viscosity-normalized temperature (Fig. 2a ), and allows structural elucidation of highly flexible, small structures 40 . The calculated hydrodynamic radii were under 1 nm and the aspect ratios reveal similar spherical oligoTEA shapes (Fig.…”

“…Oligomers were prepared as described starting with a C 8 F 17 fluorous tag 40 , 60 , 61 . The oligomer was iteratively assembled by reacting fluorous-bound allyl groups with dithiol monomers via a thiolene reaction to produce a mono-substituted thiol to be reacted in a thiol-Michael addition with an allyl acrylamide monomer.…”

1H PFG‐NMR Diffusion Study on a Sequence‐Defined Macromolecule: Confirming Monodispersity

“…More recently, an overview of the development of NMR spectroscopy with emphasis on applications in macromolecular science has been reported by Spiess . So far, there have been few reports on pulsed field gradient NMR or diffusion‐ordered spectroscopy (PFG‐NMR/DOSY) study of synthetic sequence‐defined oligomeric macromolecules …”

“…[17] So far, there have been few reports on pulsed field gradient NMR or diffusion-ordered spectroscopy (PFG-NMR/DOSY) study of synthetic sequence-defined oligomeric macromolecules. [29,30] To overcome the challenge in characterization of sequencedefined macromolecules with dispersity close to 1, the diffusion properties of a sequence-defined decamer, which serves as a model oligomer system, were investigated by 1 H PFG-NMR. A major advantage of this NMR technique in comparison with other methods is that a nondestructive and noninvasive analysis can be performed while keeping the sample intact.…”