Molecular Determinants of Specificity in the Dpr-DIP Interaction Network

Abstract

Understanding the physical and chemical principles governing specificity in protein—protein binding is important both for revealing mechanisms of molecular recognition and for designing novel biomolecular systems. The protein families Dprs and DIPs, comprised of 21 and 9 immunoglobulin superfamily (IgSF) proteins, respectively, mediate neural cell adhesions and are critical for synapse formation specificity during development in arthropods. Previous research has recently characterized the Dpr-DIP interaction network and found that each Dpr selectively interacts with specific DIPs; the synaptic connectivity pattern in the fly brain is encoded by this molecular interaction network. The goal of this project is to determine the molecular basis of the specificity of these interactions. To achieve this goal, we are computing the binding free energies of each possible Dpr-DIP interaction using both the Molecular Mechanics-Poisson Boltzmann Surface Area (MM-PBSA) approach and potential of mean force (PMF) based framework, constructed from all atom molecular dynamics (MD) simulations. We are also employing a new near-atomic level MD program, Upside, to rapidly sample possible poses. Due to the lack of high-resolution crystal structures for most of these interactions, homology modeling was used in order to generate the initial structures. The calculated binding free energies will be used to predict possible Dpr-DIP interactions. Ultimately, we hope to use our current approach to predict potential protein—protein interactions between other IgSF proteins, which make up the second largest protein family in the human proteome, and are crucial for the development and function of the nervous and immune systems.