Computational design and experimental testing of the fastest-folding ß-sheet protein
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One of the most important and elusive goals of molecular biology is the formulation of a detailed, atomic-level understanding of the process of protein folding. Fast-folding proteins with low free-energy barriers have proved to be particularly productive objects of investigation in this context, but the design of fast-folding proteins was previously driven largely by experiment. Dramatic advances in the attainable length of molecular dynamics simulations have allowed us to characterize in atomic-level detail the folding mechanism of the fast-folding all-ß WW domain FiP35. In the work reported here, we applied the biophysical insights gained from these studies to computationally design an even faster-folding variant of FiP35 containing only naturally occurring amino acids. The increased stability and high folding rate predicted by our simulations were subsequently validated by temperature-jump experiments. The experimentally measured folding time was 4.3 µs at 80 °C-about three times faster than the fastest previously known protein with ß-sheet content and in good agreement with our prediction. These results provide a compelling demonstration of the potential utility of very long molecular dynamics simulations in redesigning proteins well beyond their evolved stability and folding speed.
Originalsprog | Engelsk |
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Tidsskrift | Journal of Molecular Biology |
Vol/bind | 405 |
Udgave nummer | 1 |
Sider (fra-til) | 43-48 |
Antal sider | 6 |
ISSN | 0022-2836 |
DOI | |
Status | Udgivet - 7 jan. 2011 |
Eksternt udgivet | Ja |
ID: 37812301