ORGN 4 |
| This lecture will summarize what we have learned to date about the folding of beta-sheets utilizing numerous WW domain variants. The influence of both backbone and side-chain perturbations at nearly every position within the three-stranded beta-sheet on the kinetics and thermodynamics of beta-sheet folding have been carefully evaluated. These data reveal that the formation of loop 1 is rate limiting for folding. The incorporation of certain natural and non-natural reverse turn sequences into loop 1 increase the folding rate to that approaching the theoretical speed limit–that associated with downhill folding. The sequence of this loop has evolved for function, not maximal folding rate in the case of the PIN WW domain. Optimal reverse turns in this region also influence thermodynamic stability, however not as substantially as hydrophobic side-chain packing in the core of the beta-sheet. Hydrogen bonds also contribute to beta-sheet stability, however not all hydrogen bonds are equally energetic. In fact, an ester for amide scan of the backbone reveals that only five of the hydrogen bonds in the WW domain contribute substantially to stabilizing the folded state, those enveloped by a hydrophobic cluster. The ability to mutate both the side chain and the backbone in combination with a detailed kinetic and thermodynamic analysis of each variant has led to an unusually detailed picture of beta-sheet folding.
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Ralph F. Hirschmann Award in Peptide Chemistry
8:00 AM-12:00 PM, Sunday, 13 March 2005 Convention Center -- Ballroom 20A-B, Oral
Division of Organic Chemistry |