Project Summary This proposal examines the efficiency and selectivity of peptide transport through biological membranes. Peptides are widely used in biology to permeate through target membranes. They transport material to specific cells as well as cell compartments. They are also used as defense mechanisms against other organisms such as antimicrobial peptides, or against malignant cells (anticancer peptides). The diversity and specificity of peptide functions make them an excellent target for a study that aims to deliver material (drugs) with razor sharp accuracy into a selected cell or a cell compartment. An interdisciplinary team was assembled to study peptide interactions with biological membranes that encompass expertise in molecular dynamics simulations of biological molecules, expertise in physical chemistry experiments on biological systems that are able to pinpoint the location and measure the dynamics of a diverse set of peptides passing through different types of membranes, and expertise in biological experiments of peptide permeation into living cells. The interdisciplinary team is needed because of the tremendous complexity of biological membranes that are made of thousands types of different phospholipid molecules, and many other components such as cholesterol molecules and trans- membrane proteins. This complexity is necessary for membrane function. Novel simulation and experimental tools are developed that will make it possible to compute, predict and measure the impact of membrane and peptide variation on permeability and function. Variations in selectivity of the plasma membranes of cancer and normal cells were already illustrated and will be further investigated to elucidate specificity of molecular mechanisms and offer design principles. This project is expected to shed light on the detailed mechanisms that control the efficiency and selectivity of peptide transport through biological membranes, as well as offer avenues to impact these mechanisms.