Journal
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
Volume 105, Issue 7, Pages 2369-2374Publisher
NATL ACAD SCIENCES
DOI: 10.1073/pnas.0711908105
Keywords
activated rate; alkene peptide isosteres; molecular rate; speed limit; stability
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Funding
- NIGMS NIH HHS [GM 051105, R01 GM051105, P50 GM067082-06, P50 GM067082] Funding Source: Medline
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A kinetic and thermodynamic survey of 35 WW domain sequences is used in combination with a model to discern the energetic requirements for the transition from two-state folding to downhill folding. The sequences used exhibit a 600-fold range of folding rates at the temperature of maximum folding rate. Very stable proteins can achieve complete downhill folding when the temperature is lowered sufficiently below the melting temperature, and then at even lower temperatures they become two-state folders again because of cold denaturation. Less stable proteins never achieve a sufficient bias to fold downhill because of the onset of cold denaturation. The model, considering both heat and cold denaturation, reveals that to achieve incipient downhill folding (barrier <3 RT) or downhill folding (no barrier), the WW domain average melting temperatures have to be >= 50 degrees C for incipient downhill folding and >= 90 degrees C for downhill folding.
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