Molecular Dynamics Simulations of Self-Assembly of Nonviral Gene Delivery Complexes By Pegylated Peptides and siRNA Molecules

The design of peptide-based polyelectrolyte complexes as viable non-viral vector is of great interest in gene delivery systems due to its ability to overcome significant challenges such as biocompatibility, stability, and degradation. Molecular interactions between polyplexes formed from cationic peptide-based polymers and siRNA have been shown to largely influence the effectiveness of the therapeutic system.  Moreover, structural characteristics such as the charge density, molecular weight and changes in the physiological conditions can contribute and dictate the resulting physiochemical behavior of the siRNA/polymer polyplexes. Our studies examine molecular-level kinetic mechanisms of self-assembly by PEGylated-poly(Lysine) and siRNA molecules to form polyplexes via molecular dynamics simulations using multiscale models. We also investigate the role of external biological stimuli (e.g. pH, salt concentration, PEGylated-poly(Lysine)/SiRNA concentrations, or temperature) on stability and size distribution of the assembled complexes. Additional study is also on an analogous system of PEGylated-poly(ketalized-Serine) that has been recently shown to enhance gene delivery efficiency compared to poly(Lysine). Comparison between the two systems will enable a more comprehensive understanding of the relationship between the structural design and the biological functionality. The findings of this research will aid experimentalists by identifying optimal assembly and disassembly conditions to improve the design of polyplexes for gene therapy.