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Widespread industrial use of per- and polyfluoroalkyl substances (PFAS) as surfactants has led to global contamination of water sources with these persistent, highly stable chemicals. As a result, humans and wildlife are regularly exposed to PFAS, which have been shown to bioaccumulate and cause adverse health effects. Methods for detecting PFAS in water are currently limited and primarily utilize mass spectrometry (MS), which is time-consuming and requires expensive instrumentation. Thus, new methods are needed to rapidly and reliably assess the pollution level of water sources. While some fluorescent PFAS sensors exist, they typically function in high nanomolar or micromolar concentration ranges and focus on sensing only 1–2 individual PFAS. Our work aims to address this problem by developing a fluorescent sensor for both individual PFAS, as well as complex PFAS mixtures, and demonstrate its functionality in tap water samples. Here we show that dynamic combinatorial libraries (DCLs) with simple building blocks can be templated with a fluorophore and subsequently used as sensors to form an array that differentially detects each PFAS species and various mixtures thereof. Our method is a high-throughput analysis technique that allows many samples to be analyzed simultaneously with a plate reader. This is one of the first examples of a fluorescent PFAS sensor array that functions at low nanomolar concentrations, and herein we report its use for the rapid detection of PFAS contamination in water. 

Herein we describe the use of dynamic combinatorial chemistry to self-assemble complex coiled coil motifs. We amide-coupled a series of peptides designed to form homodimeric coiled coils with 3,5-dithiobenzoic acid (B) at the N-terminus and then allowed each B-peptide to undergo disulfide exchange. In the absence of peptide, monomer B forms cyclic trimers and tetramers, and thus we expected that addition of the peptide to monomer B would shift the equilibrium towards the tetramer to maximize coiled coil formation. Unexpectedly, we found that internal templation of the B-peptide through coiled coil formation shifts the equilibrium towards larger macrocycles up to 13 B-peptide subunits, with a preference for 4, 7, and 10-membered macrocycles. These macrocyclic assemblies display greater helicity and thermal stability relative to intermolecular coiled coil homodimer controls. The preference for large macrocycles is driven by the strength of the coiled coil, as increasing the coiled coil affinity increases the fraction of larger macrocycles. This system represents a new approach towards the development of complex peptide and protein assemblies. 

Frustrated, or nonoptimal, interactions have been proposed to be essential to a protein’s ability to display responsive behav-ior, such as allostery, conformational signaling, and signal transduction. However, the intentional incorporation of frustrated noncovalent interactions has not been explored as a design element in the field of dynamic foldamers. Here we report the design, synthesis, characterization, and MD simulations of the first dynamic water-soluble foldamer that, in response to a stimulus, exploits relief of frustration in its noncovalent network to structurally rearrange from a pleated to intercalated co-lumnar structure. Thus, relief of frustration provides the energetic driving force for structural rearrangement. This work repre-sents a previously unexplored design element for development of stimulus-responsive systems that has potential application to materials chemistry, synthetic biology, and molecular machines. 

Abstract Amide−π interactions, in which an amide interacts with an aromatic group, are ubiquitous in biology, yet remain understudied relative to other noncovalent interactions. Recently, we demonstrated that an electrostatically tunable amide−π interaction is key to recognition of histone acyllysine by the AF9 YEATS domain, a reader protein which has emerged as a therapeutic target due to its dysregulation in cancer. Amide isosteres are commonly employed in drug discovery, often to prevent degradation by proteases, and have proven valuable in achieving selectivity when targeting epigenetic proteins. However, like amide−π interactions, interactions of amide isosteres with aromatic rings have not been thoroughly studied despite widespread use. Herein, we evaluate the recognition of a series of amide isosteres by the AF9 YEATS domain using genetic code expansion to evaluate the amide isostere−π interaction. We show that compared to the amide−π interaction with the native ligand, each isostere exhibits similar electrostatic tunability with an aromatic residue in the binding pocket, demonstrating that the isosteres maintain similar interactions with the aromatic residue. We identify a urea‐containing ligand that binds with enhanced affinity for the AF9 YEATS domain, offering a promising starting point for inhibitor development. Furthermore, we demonstrate that carbamate and urea isosteres of crotonyllysine are resistant to enzymatic removal by SIRT1, a protein that cleaves acyl post‐translational modifications, further indicating the potential of amide isosteres in YEATS domain inhibitor development. These results also provide experimental precedent for interactions of these common drug discovery moieties with aromatic rings that can inform computational methods.