Ultrafast Processing in Proteins and Other Assemblies

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A residue level visualization of how protein structures change with time for transmembrane (TM) helices, fast folding proteins and elements of secondary structure will be found by two dimensional infrared spectroscopy (2D IR) a new, powerful method of structural biology. Isotopic labeling of peptides and proteins enhances the spatial resolution of 2D IR and extends it to larger peptides. Weak bonds involved at the helix-helix interfaces of TM sections of Glycophorin A will be accessed to obtain the motions of groups in the interface regions and discover how they stabilize helix-helix interactions in TM proteins. 2D IR exposes lipid fluctuations in terms of spatial arrangements across the membrane. 2D IR of hydrophobic effects, polarity, hydrogen bonding and other weak interactions between buried residues enlighten the mechanisms and structural basis of helix association. The 2D IR with multiple IR frequencies, accesses the hydrophobic interface, correlations between fluctuations at different spatial locations and the N-H/N-D exchange in transmembrane helices. Protein subdomains that fold independently are important tools for solving the folding problem. 2D IR on fast non-exponential folders will permit access to the real time evolution of secondary structure and challenge all atom molecular dynamics of the villin headpiece from the actin-bundling protein villin, which is implicated in the epithelium of the gut and kidney. The folding pathway will be accessed by 2D IR of isotope labeled helices and hydrophobic core. On-pathway intermediates in the redox protein, cytochrome-c, will be examined with novel temperature induced pH jumps. A description of the folding of designed peptides will be sought by 2D IR to visualize how they assemble and strengthen relations to theory. The research involves membrane proteins which are vital components of the cell physiology: they include cell-surface receptors, ion channels, transporters and redox proteins. Integral membrane proteins account for nearly one-quarter of all coding sequences in higher organisms, and more than half of all commercial drugs target this class of proteins. Despite this, study of their 3D structures and their dynamics remains limited. Protein folding is highly relevant because it is a key step in the conversion of genetic information into biological function of all types and therefore its control is an essential part of understanding human health. *