Ligand–Receptor Interaction Modulates the Energy Landscape of Enzyme-Instructed Self-Assembly of Small Molecules

Abstract

The concurrence of enzymatic reaction and ligand–receptor interactions is common for proteins, but rare for small molecules and has yet to be explored. Here we show that ligand–receptor interaction modulates the morphology of molecular assemblies formed by enzyme-instructed assembly of small molecules. While the absence of ligand–receptor interaction allows enzymatic dephosphorylation of a precursor to generate the hydrogelator that self-assembles to form long nanofibers, the presence of the ligand–receptor interaction biases the pathway to form precipitous aggregates containing short nanofibers. While the hydrogelators self-assemble to form nanofibers or nanoribbons that are unable to bind with the ligand (i.e., vancomycin), the addition of surfactant breaks up the assemblies to restore the ligand–receptor interaction. In addition, an excess amount of the ligands can disrupt the nanofibers and result in the precipitates. As the first example of the use of ligand–receptor interaction to modulate the kinetics of enzymatic self-assembly, this work not only provides a solution to evaluate the interaction between aggregates and target molecules but also offers new insight for understanding the emergent behavior of sophisticated molecular systems having multiple and parallel processes.

Supramolecular catalysis and dynamic assemblies for medicine

“…Moreover, the concurrence of enzymatic reaction and ligand–receptor interactions provides a new strategy to design sophisticated molecular systems under dual controls. 50 With more understanding of self-assembling process and crystal structures of biomacromolecules in different intermediate states at the atomic level, dynamic assemblies provide a platform technology for developing next generation biomaterials with precisely controlled functions. In addition, to address these challenges, it requires the interdisciplinary collaboration of chemists, molecular biologists, physicists, physiologists, structural biologists, clinicians as well as computer scientists.…”

Nanoscale Self-Assembly for Therapeutic Delivery

“…Formation of the most of the biological nanostructures is the outcome of the self-assembly such as construction of cell membranes by assembly of phospholipid bilayers, helical structure of DNA, folding of polypeptide chains, etc. The interaction of a ligand with its receptor is also attributed to self-assembly (Haburcak et al, 2016;Azevedo and da Silva, 2018). It also accounts for the development of molecular crystals, self-assembled monolayers, phase separated polymers, and colloids (Busseron et al, 2013;Mendes et al, 2013;Du et al, 2015;Mattia and Otto, 2015;Habibi et al, 2016;Haburcak et al, 2016;Stoffelen and Huskens, 2016;Sun et al, 2017;Azevedo and da Silva, 2018).…”

Enzymatic Noncovalent Synthesis of Supramolecular Soft Matter for Biomedical Applications

“…69,70 Such ligand-receptor interactions are also able to regulate the supramolecular assemblies formed by ALP-catalyzed selfassembly. 63 As shown in Figure 2E, a small peptide, Nap-FFYGGaa (''a'' represents D-alanine), self-assembles to form nanofibrils after adding ALP to a solution of Nap-FFY p GGaa. The co-addition of vancomycin and ALP results in supramolecular assemblies that depend on the concentration of vancomycin.…”