Characterization of the folding energy landscapes of computer generated proteins suggests high folding free energy barriers and cooperativity may be consequences of natural selection

TitleCharacterization of the folding energy landscapes of computer generated proteins suggests high folding free energy barriers and cooperativity may be consequences of natural selection
Publication TypeJournal Article
Year of Publication2004
AuthorsScalley-Kim, M., & Baker D.
JournalJournal of molecular biology
Volume338
Issue3
Pagination573-83
Date Published2004 Apr 30
ISSN0022-2836
KeywordsComputational Biology, Kinetics, Molecular Sequence Data, Primary Publication, Protein Denaturation, Protein Engineering, Protein Folding, Protein Structure, Tertiary, Proteins, Selection, Genetic
Abstract

To determine the extent to which protein folding rates and free energy landscapes have been shaped by natural selection, we have examined the folding kinetics of five proteins generated using computational design methods and, hence, never exposed to natural selection. Four of these proteins are complete computer-generated redesigns of naturally occurring structures and the fifth protein, called Top7, has a computer-generated fold not yet observed in nature. We find that three of the four redesigned proteins fold much faster than their naturally occurring counterparts. While natural selection thus does not appear to operate on protein folding rates, the majority of the designed proteins unfold considerably faster than their naturally occurring counterparts, suggesting possible selection for a high free energy barrier to unfolding. In contrast to almost all naturally occurring proteins of less than 100 residues but consistent with simple computational models, the folding energy landscape for Top7 appears to be quite complex, suggesting the smooth energy landscapes and highly cooperative folding transitions observed for small naturally occurring proteins may also reflect the workings of natural selection.

Alternate JournalJ. Mol. Biol.
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