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Protein unfolding rates correlate as strongly as folding rates with native structure
Author(s) -
Broom Aron,
Gosavi Shachi,
Meiering Elizabeth M.
Publication year - 2015
Publication title -
protein science
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 3.353
H-Index - 175
eISSN - 1469-896X
pISSN - 0961-8368
DOI - 10.1002/pro.2606
Subject(s) - protein folding , topology (electrical circuits) , native state , contact order , folding (dsp implementation) , protein engineering , chemistry , denaturation (fissile materials) , protein stability , stability (learning theory) , chemical physics , crystallography , biophysics , biology , computer science , mathematics , biochemistry , enzyme , combinatorics , machine learning , electrical engineering , nuclear chemistry , engineering
Although the folding rates of proteins have been studied extensively, both experimentally and theoretically, and many native state topological parameters have been proposed to correlate with or predict these rates, unfolding rates have received much less attention. Moreover, unfolding rates have generally been thought either to not relate to native topology in the same manner as folding rates, perhaps depending on different topological parameters, or to be more difficult to predict. Using a dataset of 108 proteins including two‐state and multistate folders, we find that both unfolding and folding rates correlate strongly, and comparably well, with well‐established measures of native topology, the absolute contact order and the long range order, with correlation coefficient values of 0.75 or higher. In addition, compared to folding rates, the absolute values of unfolding rates vary more strongly with native topology, have a larger range of values, and correlate better with thermodynamic stability. Similar trends are observed for subsets of different protein structural classes. Taken together, these results suggest that choosing a scaffold for protein engineering may require a compromise between a simple topology that will fold sufficiently quickly but also unfold quickly, and a complex topology that will unfold slowly and hence have kinetic stability, but fold slowly. These observations, together with the established role of kinetic stability in determining resistance to thermal and chemical denaturation as well as proteases, have important implications for understanding fundamental aspects of protein unfolding and folding and for protein engineering and design.