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  1. Enzymes have an extraordinary ability to utilize aromatic interactions for molecular recognition and catalysis. We here report molecularly imprinted nanoparticle receptors. The aromatic “wall” material in the imprinted binding site is used to enhance the molecular recognition of aromatic guests that have similar charges, shapes, and sizes but differ in π-electron density. Additionally, aromatic interactions are employed to activate an electron-rich aryl leaving group on a glycoside, mimicking the nucleoside hydrolase of the parasite Trypanosoma vivax. 
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    Free, publicly-accessible full text available April 5, 2025
  2. Pyk2 is a multi-domain non-receptor tyrosine kinase that serves dual roles as a signaling enzyme and scaffold. Pyk2 activation involves a multi-stage cascade of conformational rearrangements and protein interactions initiated by autophosphorylation of a linker site. Linker phosphorylation recruits Src kinase, and Src-mediated phosphorylation of the Pyk2 activation loop confers full activation. The regulation and accessibility of the initial Pyk2 autophosphorylation site remains unclear. We employed peptide-binding molecularly imprinted nanoparticles (MINPs) to probe the regulatory conformations controlling Pyk2 activation. MINPs differentiating local structure and phosphorylation state revealed that the Pyk2 autophosphorylation site is protected in the autoinhibited state. Activity profiling of Pyk2 variants implicated FERM and linker residues responsible for constraining the autophosphorylation site. MINPs targeting each Src docking site disrupt the higher-order kinase interactions critical for activation complex maturation. Ultimately, MINPs targeting key regulatory motifs establish a useful toolkit for probing successive activational stages in the higher-order Pyk2 signaling complex. 
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    Free, publicly-accessible full text available May 8, 2025
  3. Abstract

    Molecular recognition of proteins is key to their biological functions and processes such as protein–protein interactions (PPIs). The large binding interface involved and an often relatively flat binding surface make the development of selective protein-binding materials extremely challenging. A general method is reported in this work to construct protein-binding polymeric nanoparticles from cross-linked surfactant micelles. Preparation involves first dynamic covalent chemistry that encodes signature surface lysines on a protein template. A double molecular imprinting procedure fixes the binding groups on the nanoparticle for these lysine groups, meanwhile creating a binding interface complementary to the protein in size, shape, and distribution of acidic groups on the surface. These water-soluble nanoparticles possess excellent specificities for target proteins and sufficient affinities to inhibit natural PPIs such as those between cytochrome c (Cytc) and cytochrome c oxidase (CcO). With the ability to enter cells through a combination of energy-dependent and -independent pathways, they intervene apoptosis by inhibiting the PPI between Cytc and the apoptotic protease activating factor-1 (APAF1). Generality of the preparation and the excellent molecular recognition of the materials have the potential to make them powerful tools to probe protein functions in vitro and in cellulo.

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  4. Abstract

    Most nanomedicines require efficient in vivo delivery to elicit meaningful diagnostic and therapeutic effects. However, en route to their intended tissues, systemically administered nanoparticles often encounter delivery barriers. To describe these barriers, the term “nanoparticle blood removal pathways” (NBRP) is proposed, which summarizes the interactions between nanoparticles and the body's various cell‐dependent and cell‐independent blood clearance mechanisms. Nanoparticle design and biological modulation strategies are reviewed to mitigate nanoparticle‐NBRP interactions. As these interactions affect nanoparticle delivery, the preclinical literature from 2011–2021 is studied, and the nanoparticle blood circulation and organ biodistribution data are analyzed. The findings reveal that nanoparticle surface chemistry affects the in vivo behavior more than other nanoparticle design parameters. Combinatory biological‐PEG surface modification improves the blood area under the curve by ≈418%, with a decrease in liver accumulation of up to 47%. A greater understanding of nanoparticle‐NBRP interactions and associated delivery trends will provide new nanoparticle design and biological modulation strategies for safer, more effective, and more efficient nanomedicines.

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    Free, publicly-accessible full text available February 1, 2025
  5. Protection/deprotection is a powerful strategy in the total synthesis of complex organic molecules but similar tools are nearly absent in enzymatic reactions. We here report supramolecular protective receptors that outcompete an enzyme in the binding of oligosaccharides. The strong binding inhibits the enzymatic reaction and addition of an even stronger ligand for the receptor releases the substrate. These receptors could be used to control products from the same substrate/enzyme mixture and regulate enzymatic reactions reversibly. 
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  6. Regulation of enzyme activity is key to dynamic processes in biology but is difficult to achieve with synthetic systems. We here report molecularly imprinted nanoparticles with strong binding for the N- and C-terminal peptides on lysozyme. Binding affinity for the enzyme correlated with conformational flexibility of the peptides in the protein structure. Significantly, binding at the C-terminus of lysozyme enhanced the performance of the enzyme at elevated temperatures and that at the N-terminus lowered the enzyme activity. These nanoparticles, when clicked onto magnetic nanoparticles, could also be used to fish out the protein of interest from a mixture in a single step. 
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