Computational design and experimental testing of the fastest-folding ß-sheet protein
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Computational design and experimental testing of the fastest-folding ß-sheet protein. / Piana, Stefano; Sarkar, Krishnarjun; Lindorff-Larsen, Kresten; Guo, Minghao; Gruebele, Martin; Shaw, David E.
In: Journal of Molecular Biology, Vol. 405, No. 1, 07.01.2011, p. 43-48.Research output: Contribution to journal › Journal article › Research › peer-review
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TY - JOUR
T1 - Computational design and experimental testing of the fastest-folding ß-sheet protein
AU - Piana, Stefano
AU - Sarkar, Krishnarjun
AU - Lindorff-Larsen, Kresten
AU - Guo, Minghao
AU - Gruebele, Martin
AU - Shaw, David E
N1 - Copyright © 2010 Elsevier Ltd. All rights reserved.
PY - 2011/1/7
Y1 - 2011/1/7
N2 - 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.
AB - 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.
U2 - 10.1016/j.jmb.2010.10.023
DO - 10.1016/j.jmb.2010.10.023
M3 - Journal article
C2 - 20974152
VL - 405
SP - 43
EP - 48
JO - Journal of Molecular Biology
JF - Journal of Molecular Biology
SN - 0022-2836
IS - 1
ER -
ID: 37812301