Rational Design of a Tetrameric Protein to Enhance Interactions between Self‐Assembled Fibers Gives Molecular Hydrogels

Abstract

Molecular hydrogels have attracted extensive research interest in recent years because of their inherent properties (e.g., formation by the self-assembly of small molecules and their gel–sol/sol–gel phase transitions can be easily manipulated by external stimulus). They have shown great potential in fields such as three-dimensional (3D) cell culture and controlled drug delivery. During the formation of a molecular hydrogel, a small molecule (molecular hydrogelator) needs to selfassemble into a 3D matrix of nanofibers, nanorods, or nanospheres that can hold water molecules within the cavities of the 3D matrix. To form the 3D matrix, there should be strong or at least medium interactions between self-assembled nanostructures. Otherwise, nanostructures with weak interactions between them will only form dispersions or solutions in the aqueous phase. Actually, there are many examples of this kind of self-assembled system that lack strong interactions between the self-assembled structures. This type of solution/dispersion containing self-assembled nanostructures could change to a hydrogel if the interaction between the nanostructures could be enhanced. For example, several groups have demonstrated that zinc and calcium ions can be used to cross-link self-assembled nanofibers to form molecular hydrogels. In this study, we rationally designed a fusion protein with four binding sites and used the protein– peptide interaction to enhance interactions between selfassembled nanofibers, thus leading to the formation of molecular hydrogels (Figure 1). There are only a few examples of polymeric hydrogels formed by specific protein–peptide interactions. Specific protein–peptide interaction has also been used to direct self-