| Scaffolding proteins serve as regulators of signaling pathways, binding to and interacting with various protein partners involved in these pathways. Their ability to regulate signaling pathways through these interactions is dependent on several protein-protein interaction modules. These modules, such as PDZ domains (postsynaptic density 95/discs large/zona occludens-1) and SH3 (Src homology 3) domains, are integral to the function of scaffolding proteins, and, although much is known about the modules as discrete domains, they are often separated by flexible linker regions that make a detailed molecular understanding of the interactions between the domains within these proteins a difficult task. To date, insight into these intra-protein interactions of scaffolding proteins are limited largely to PDZ-PDZ dimers, which are separated by relatively short linker regions. This paper proposes a novel methodology, B2C, for studying the interactions and orientations between these scaffolding protein domains. Using only the most general features of these domains, it is possible to generate unbiased starting structures, giving information about potential topological orientations between them that can be further refined through molecular mechanics calculations (energy minimization and molecular dynamics). |
