Hydrophobic Interaction and its Small Molecule effect

Protein stabilization has a crucial rule sustaining biological functionality, disease prevention, and pharmaceutical formulation stabilization, and yet its stabilization mechanism by small molecules such as amino acids is not fully understood. In this work, we proposed a mixed ligand-protected gold nanoparticle model system that encompasses fundamental protein interactions to study the colloidal interaction change in such a phenomenon. We find the amino acids stabilize colloids in a general term including non-biological nanoparticles, various proteins, and plasmid DNA, through a weak interaction on hydrophobic patches on these colloids. A theoretical framework is developed and validated experimentally that can describe the interaction changes among the colloids studied, due to the amino acids. Our studies show that proline reduces attractive interactions in colloids, which are strongly influenced by hydrophobic interactions. Using nanoparticles with varying hydrophobicity, we find that greater hydrophobicity leads to more aggregation and increased proline stabilization. In a gold nanoparticle system dominated by electrostatic repulsion, proline significantly shortens the decay length of attractive forces, with minimal effect on repulsive forces. We also examined the role of water structure in this stabilization. While proline alters water structure, no correlation was found between these changes and proline's stabilizing properties, suggesting that direct interaction with colloids is key. This thesis provides new insights into protein stabilization from a colloidal perspective. This work here in provides insights to rethink about protein stabilization effect from a colloidal point of view, while also encompass the aspect co-solvent change on the bulk structure of water to understand the phenomenon of small molecules stabilizing proteins.