MOLECULAR STRUCTURE OF BIOLOGICAL MOLECULES

Yale University, New Haven CT

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Abstract

We seek to establish the structures of several simple oligomeric complexes of transmembrane helices using several strategies, including a combination of mutagenesis and modeling, the use of multi-dimensional heteronuclear NMR, and, perhaps, crystallography. At the same time, we will use sequence variation to probe the chemical interactions responsible for stable association of helical structures. Measurements using small angle x-ray scattering, calorimetry, and electrophoresis will define differences in stability arising from specific amino acid substitutions. These will be compared with predicted differences based on computational modeling via energy minimization, molecular dynamics, and simulated annealing. Initially, work will focus on pentamers formed by phospholamban transmembrane helices, the dimers of glycophorin helices, and transmembrane segments from the T cell receptor. Combining knowledge of the structures with an understanding of the chemical principles of their formation will lead to improved predictive strategies for the structures of helical membrane proteins.