This proposal seeks to calculate the properties of polymeric electrolytes that are central to bio-medically relevant systems, such as drug delivery, gene knockout, and viral replication. The goal of the computations is to establish a new calculational procedure capable of predicting the atomistic structure, thermodynamic stability, and environmental responses of polyelectrolyte complexes under various aqueous conditions. In addition, the PI will seek to validate the calculations, not just by comparison to highly idealized experimental systems, but to actually predict the properties of such systems as polypeptide-polypeptide interactions, which cannot otherwise be accomplished with conventional computational methods. This is an ambitious proposal that can have a significant impact on the fundamental understanding (and therefore rational design) of biologically and bio-medically important molecular systems that can lead to the design of improved drug delivery systems and gene-based technologies.
At present, most of existing studies are based on conventional polymer theories that ignore local density inhomogeneity, explicit solvent effects, and long-ranged intra-chain and electrostatic correlations. The simplistic representations of the polymeric systems are useful to establish the basic rules of complex formation as well as qualitative or occasionally semi-quantitative features of the phase behavior of bulk polyelectrolyte systems. But the low-resolution structure and bulk phase transitions predicted by mean-field methods are often insufficient to describe the structure-activity relationships desired for practical applications. Development of reliable computational tools to predict the interaction between oppositely charged polymers lags far behind practical applications. In order to address these deficiencies, this proposal will attempt to advance the understanding of polyelectrolyte formation via a theoretical approach built upon recent progress from the PI's group on high-throughput free-energy calculations within the framework of the classical density functional theory (DFT), which will be generalized for polymeric systems using a new perturbation method proposed in this work. The goal of this project is to establish a new computational procedure capable of predicting the atomistic structure, thermodynamic stability, and environmental responses of polyelectrolyte complexes in various aqueous conditions. In addition, the PI will seek to validate the theory, not just by comparison to highly idealized experimental systems, but to actually predict the properties of complex molecular systems, such as polypeptide-polypeptide interactions, that cannot otherwise be accomplished with conventional computational methods. The proposed work will also identify and examine the thermodynamics that affect the stability and delivery efficacy of siRNA (small interfering RNA), a type of RNA used for knock-down of specific genes.
