| The aim of the proposed research is to develop and apply a computational tool to study protein-protein interactions and the stability and dynamics of protein complexes, based on molecular dynamics simulations. Two major objectives will be followed: 1. To improve and benchmark the coarse grained Martini model to study protein-protein interactions: One great challenge in understanding biological processes lies in the underlying protein interacting networks and their dynamics. The transient nature and complexity of most protein complexes makes their experimental characterization extremely difficult. Computational methods propose an alternative approach that has become extremely valuable. Notably the recent development of coarse grained (CG) models allows the simulation of systems of size and for time scales becoming relevant to biological phenomena. The focus of the proposed research will be to benchmark the current Martini CG force field (developed in our laboratory) against a large data-base of protein complexes. The main objective is to optimize the force field using a dynamic elastic network approach with an emphasis on the inclusion of conformational changes/flexibility into the model. 2. To study the spontaneous formation and the dynamics of protein complexes: We will pursue our long-time efforts in understanding the forces that govern the formation and dynamics of biomolecular assemblies. In this project we will more particularly focus on processes in which proteins are important and elucidate the forces involved. We will investigate the fundamental driving forces of G Protein-Coupled Receptor (GPCRs) self-assembly and evaluate the relative contribution of the continuum elastic properties of the membrane bilayer and specific protein-lipid and/or protein-protein interactions to the propensity of these proteins to form dimers and larger aggregates. The binding free energy of different rhodopsin-rhodopsin (the visual pigment) interfaces will be evaluated. Another challenging task will be the prediction of the interface and the stoichiometry of the complex between rhodopsin and its cognate G Protein, transducin, for which the actual interface is not known at the atomic level. Moreover, there is a large body of evidence indicating the presence of conformational changes upon activation and/or binding of both proteins. This will be an excellent test case for the improved protein force field in which conformational changes are allowed. The main partners in this proposal will be: Prof. A.E. Mark (Univ. of Queensland-Australia) and Prof. M. Ceruso (City Univ. of New York-USA), on the force field development, and Prof. T. Sakmar (Rockefeller Univ. New York-USA), on experimental characterization of rhodopsin and transducin interactions. |
