Molecular Dynamic Simulation Study on Soy Protein As Drug Delivery Vehicle

Recently, the controlled drug delivery technology has been widely investigated to address and treat challenging diseases such as cancer, ADIS etc. Nanoparticle-based drug delivery systems are extensively explored and found to possess certain advantages over traditional delivery systems, such as greater stability during storage, stability in vivo after administration and ease of scale-up during manufacture. While the techniques have proven beneficial in disease treatment and diagnostics, there are still grand needs to develop different nanoparticle systems for various drugs.

Bio-based materials, such as plant protein, have gained great attention as drug delivery vehicles among the available potential colloidal carrier systems, due to their low cytotoxicity, abundance, renewability, diverse functional groups and interactions, and high drug loading capacity, etc. Soy protein is one of the promising candidates that can be extensively used as carrier for various drugs, because of its highly diverse molecule structures and interactions, e.g. polar/non-polar residues, hydrogen bonds, ionic interactions, hydrophobic interactions, disulfide bonds, etc. Although previous experimental results have demonstrated the potential of the protein as drug carrier, the underlying mechanisms of the attachment and release of drugs remain unclear, which is challenging to study directly through experimental approaches. Atomic-resolution molecular dynamics (MD) simulations is a powerful tool in the community of physics, chemistry and material science and can provide insights in understanding the molecular interactions between proteins and drugs.

In this study, MD simulations are adopted to study the mechanisms of the 11S molecule of soy protein as drug delivery vehicle. Two types of anticancer drugs are selected as the drug systems, i.e. allyl isothiocyanate (AITC) and doxorubicin (DOX). The adsorption processes of drugs on the protein are explored. The intermolecular interaction energies are analyzed to reveal the fundamental interactions that control the drug adsorption behaviors, and to determine the active sites on the protein surface. The loading efficiencies are calculated and compared with experiments. Furthermore, two types of denaturation conditions, including heat denaturation and breaking of disulfide bonds, are utilized to vary the microstructures of the protein carrier and improve their loading properties.

It is found that, for the AITC system, both nonpolar and polar residues of protein have the ability to adsorb AITCs; particularly, the polar residues serve as the primary active sites for the stable attachment of the drug molecules through the electrostatic (dipole-dipole) interactions. For the DOX system, however, the main driving force become the π-π stacking (the van der Waals interactions) among the aromatic rings of DOX and protein. In addition to pristine protein, two different denaturation processes, including heat denaturation and the breaking of disulfide bonds, are used to modify the microstructures and loading properties of the protein carrier. Both denaturation approaches are found to be able to increase the exposure of active sites, therefore, enhance the loading efficiency of the protein carriers.