Cationic chitosan, a naturally degradable and biocompatible polysaccharide, has shown considerable promise as a drug delivery system. However, its limited solubility in water at neutral and alkaline pH has restricted its broader application. To overcome this challenge, various chemical modification strategies have been explored to enhance the solubility of chitosan. One such strategy involves the development of chitosan-deoxycholic acid-polyacrylic acid (CDP) copolymers, which are novel amphiphilic derivatives of chitosan that exhibit excellent water solubility and self-assembly properties. Herein, we investigated the potential of CDP as an anionic carrier for two model proteins: the positively charged Lysozyme and the negatively charged Pyrazinamidase. The objective of this investigation is to elucidate the role of electrostatic interactions between the copolymer and the proteins during the drug encapsulation process. A combined approach utilizing experimental techniques and molecular dynamics (MD) simulations was used to investigate the interactions between the polymer and the proteins, as well as any potential structural changes to the proteins. The results suggest contrasting binding mechanisms for the two proteins: Lysozyme being entrapped within the cationic polymer network and Pyrazinamidase being adsorbed onto the surface of the polymeric assemblies. Binding energy calculations revealed favorable physical interactions between CDP and Lysozyme, while Pyrazinamidase exhibited unfavorable binding. These findings demonstrated that CDP may serve as a promising carrier for positively charged drugs due to its favorable interactions and potential entrapment within the polymer network. The favorable interactions observed between CDP and Lysozyme suggest that CDP could be further explored as a delivery system for positively charged therapeutic proteins.
