Electrostatic and hydrophobic interaction cooperative nanochaperone regulates protein folding

Abstract

Natural molecular chaperones utilize spatially ordered multiple molecular forces to effectively regulate protein folding. However, synthesis of such molecules is a big challenge. The concept of “aggregate science” provides insights to construct chemical entities (aggregates) beyond molecular levels to mimic both the structure and function of natural chaperone. Inspired by this concept, herein we fabricate a novel multi‐interaction (i.e., electrostatic and hydrophobic interaction) cooperative nanochaperone (multi‐co‐nChap) to regulating protein folding. This multi‐co‐nChap is fabricated by rationally introducing electrostatic interactions to the surface (corona) and confined hydrophobic microdomains (shell) of traditional single‐hydrophobic interaction nanochaperone. We demonstrate that the corona electrostatic attraction facilitates the diffusion of clients into the hydrophobic microdomains, while the shell electrostatic interaction balances the capture and release of clients. By finely synergizing corona electrostatic attraction with shell electrostatic repulsion and hydrophobic interaction, the optimized multi‐co‐nChap effectively facilitated de novo folding of nascent polypeptides. Moreover, the synergy between corona electrostatic attraction, shell electrostatic attraction and shell hydrophobic interaction significantly enhanced the capability of multi‐co‐nChap to protect native proteins from denaturation at harsh temperatures. This work provides important insights for understanding and design of nanochaperone, which is a kind of ordered aggregate with chaperone‐like activity that beyond the level of single molecule.

Mechanism of Protein Aggregation Inhibition by Arginine: Blockage of Anionic Side Chains Favors Unproductive Encounter Complexes

“…57 Is the native state destabilization by Arg•HCl seen here and elsewhere 62 consistent with its use as an excipient in biopharmaceutical formulations? 26,30,42,45,48 It would be counterproductive to employ an excipient that suppresses aggregation while causing unfolding (and thus protein deactivation). Luckily, destabilization of the native state by 1 M Arg•HCl (or 1 M Gdn•HCl) is insufficient for causing room temperature unfolding of Mb (Figure S4) and other proteins.…”

“…Given the chemical diversity of existing aggregation inhibitors, ,,− it cannot be expected that the mechanism uncovered here for Arg + and Gdn + equally applies to all other inhibitors. However, the blockage of protein–protein interaction sites by competitive binding is a common theme for some of them.…”

“…The many detrimental aspects of protein aggregation have sparked interest in strategies that inhibit aggregation. , Molecular chaperones are proteins that sequester aggregation-prone chains and promote their proper folding. ,− Chemical chaperones are natural or synthetic aggregation inhibitors − ranging from nanoparticles , to low MW additives such as amino acids, sugars, surfactants, alcohols, salts, and nucleoside triphosphates. ,,,− Mixtures of these compounds serve as excipients in biopharmaceutical formulations, where they promote protein longevity . The optimization of such formulations requires time-consuming trial-and-error assays. − A better understanding of aggregation inhibition would help streamline the excipient screening process …”

“…32,33 Molecular chaperones are proteins that sequester aggregationprone chains and promote their proper folding. 10,34−39 Chemical chaperones are natural or synthetic aggregation inhibitors 40−43 ranging from nanoparticles 42,44 to low MW additives such as amino acids, sugars, surfactants, alcohols, salts, and nucleoside triphosphates. 26,30,42,45−47 Mixtures of these compounds serve as excipients in biopharmaceutical formulations, where they promote protein longevity.…”

Dynamic Near‐Infrared Circularly Polarized Luminescence Encoded by Transient Supramolecular Chiral Assemblies

“…Amphiphilic self‐assembly‐induced single‐fluorophore‐based multicolour fluorescence . The synergy between electrostatic and amphiphilic interactions plays an important role in the fabrication of nano‐ and mesoscale architectures, such as proteins, lipid bilayers, and microtubules, in living organisms [50–52] . Inspired by this, we designed compound 1 by incorporating two chains containing cationic moieties onto a pyrene core to i) tune the amphiphilicity to facilitate its assembly in water or aqueous solution and ii) provide electrostatic binding sites for ATP to construct chiral assemblies [45] .…”