The long-term research goal of our lab is to apply computer modeling to gain insight into cellular signal transduction pathways, specifically to provide deeper insight into both the normal and aberrant subcellular targeting of domains contained in proteins involved in macromolecular complexes that function in a variety of biological processes. Our current focus is on understanding the molecular basis of interactions of specialized protein domains like the pleckstrin homology (PH) domain with lipids and protein partners that contribute to their subcellular localization and function. The protein/membrane and protein/protein complexes that function in signaling pathways are often not amenable to traditional structure determination. A novel feature of our approach is the integration of bioinformatics tools to analyze genomic data with detailed computer calculations of the physical interactions. Therefore, the computational models that we derive provide novel insights into the molecular basis of the formation and regulation of these complexes and, thus, allow us to suggest rational and experimentally testable predictions as to their function. In addition, our computational analysis can be successfully extended to a genome-wide level, allowing us to analyze emerging families of specialized protein domains with multiple roles at the whole genome level.