Theoretical Studies of Membrane Proteins

The objective of this project is to develop and test methods for the homology modeling of membrane proteins. The homology modeling of soluble proteins and membrane proteins are areas that have developed quite independently, in part because of the vast difference in the quantity of structural information that has been available for both. In the case of soluble proteins the development and validation of computational tools have benefited from the availability of a large number of three-dimensional structures. For example, it has been possible to build models and then test them either in blind prediction as in the CASP experiment (Critical Assessment of Structure Prediction) or by comparing "predictions" of known structures to experimental structures in an unbiased fashion. The increasing number of membrane protein structures that are becoming available suggests that a similar kind of validation is now possible for this class of proteins. The central goal of this research is the development of a new battery of software tools that will allow researchers to build models and to evaluate them in an unbiased fashion. A key element of the research is the construction of models for membrane proteins of known structure based on the coordinates of related proteins. The ability of different energy functions to distinguish the decoy from the native conformation will be tested. The ability to predict the correct orientation of the protein with respect to the lipid bilayer will also be tested. The modeling approach to be taken is based on methods that have been developed in the PI's lab in studies of soluble proteins. These include novel tools to predict the conformation of amino acid side chains on a fixed backbone, novel loop prediction methods and a new model building program. A key element of the research is the use of physical chemical-based energy criteria to evaluate the relative conformational energies of different models for a given protein. Refined energetic methods suitable for membrane proteins will be developed as the research progresses and will be combined with criteria for helix packing derived from the growing database of membrane protein structures. The broader impact of the research includes the development of software tools that are likely to be widely used in basic research and in a variety of technological applications. The research will also provide a platform for the training of women and minority scientists, a tradition in the lab for some time.