This Program supports the study of macromolecules, such as catalytic RNAs, and macromolecular assemblies like the ribosome and the plasma membrane. The RNAS, ribonucleoproteins, and enzymes responsible for gene expression, the proteins that regulate expression, and membrane proteins will be emphasized over the next five years. The primary techniques used to characterize these molecules will be single-crystal X- ray diffraction, where possible, and X-ray scattering and high-resolution cryoelectron microscopy when only solutions or partially ordered samples are available. This Program will also support studies of the motions that occur both within biological macromolecules and between components of macromolecular assemblies as they function. Motion can be inferred from confidential differences observed when time average structures are determined for a given macromolecule under different environmental conditions or in different states of ligation. Of special interest are the motions that occur: (1) during the catalytic cycles of RNA and DNA polymerases and other enzymes, (2) in the course of protein synthesis as the ribosome proceeds through its elongation cycle, and (3) during the insertion of intrinsic membrane proteins into lipid bilayers and the passage of secreted proteins through membranes. Theoretical investigations will also be undertaken of protein-membrane interactions, and work will continue on improving the computational procedures used to obtain structures both by S-ray crystallography and by NMR.
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