The discovery of RNA interference mediated gene silencing by double-stranded RNA is one of the most exciting recent developments in the biological and biomedical sciences. RNAi utilizes a pathway whereby a double-stranded small interfering RNA (siRNA) targets and destroys complementary mRNA in eukaryotic cells to regulate gene expression. Since its discovery just over a decade ago scientists have investigated the potential use of siRNA-based treatment of many diseases such as cancer, liver cirrhosis, hepatitis B, human papillomavirus, and hypercholesterolemia. In principle, siRNA has much broader therapeutic applications than other types of drugs because siRNA can be synthetically designed to silence any gene via the RNAi machinery. Therefore, the primary challenge for therapeutic applications is efficient and non-toxic delivery of siRNA to cells within tissues of interest. The research goal of this CDI project is to design efficient delivery systems for siRNA via supercomputer simulations. Multimillion-atom simulations are performed to study: (1) the effect of siRNAs on the molecular structure of lipid membranes and how structural changes affect the membrane permeability; (2) molecular mechanisms by which siRNA molecules attached to gold nanoparticles cross the membrane and go into a cell; and (3) delivery of siRNAs encapsulated in liposomes by ultrasound. Computational technologies will be used to enable automated design of efficient siRNA delivery systems. This project is promoting scholastic and professional excellence among students. A dual-degree program has been established which gives students the opportunity to obtain a Ph.D. in the physical sciences or an engineering discipline and an M.S. in computer science with specialization in high performance computing and simulations. This research team will also organize computational science workshops for undergraduate students and faculty mentors from Historically Black Colleges and Universities and Minority Serving Institutions.