Smooth Functional Transition along a Mutational Pathway with an Abrupt Protein Fold Switch.
Author
Summary, in English
Recent protein design experiments have demonstrated that proteins can migrate between folds through the accumulation of substitution mutations without visiting disordered or nonfunctional points in sequence space. To explore the biophysical mechanism underlying such transitions we use a three-letter continuous protein model with seven atoms per amino acid to provide realistic sequence-structure and sequence-function mappings through explicit simulation of the folding and interaction of model sequences. We start from two 16-amino-acid sequences folding into an α-helix and a β-hairpin, respectively, each of which has a preferred binding partner with 35 amino acids. We identify a mutational pathway between the two folds, which features a sharp fold switch. By contrast, we find that the transition in function is smooth. Moreover, the switch in preferred binding partner does not coincide with the fold switch. Discovery of new folds in evolution might therefore be facilitated by following fitness slopes in sequence space underpinned by binding-induced conformational switching.
Publishing year
2014
Language
English
Pages
1217-1225
Publication/Series
Biophysical Journal
Volume
107
Issue
5
Document type
Journal article
Publisher
Cell Press
Topic
- Biophysics
Status
Published
ISBN/ISSN/Other
- ISSN: 1542-0086