Smooth Functional Transition along a Mutational Pathway with an Abrupt Protein Fold Switch.

Research output: Contribution to journalArticle

Abstract

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.

Details

Authors
  • Christian Holzgräfe
  • Stefan Wallin
Organisations
Research areas and keywords

Subject classification (UKÄ) – MANDATORY

  • Biophysics
Original languageEnglish
Pages (from-to)1217-1225
JournalBiophysical Journal
Volume107
Issue number5
Publication statusPublished - 2014
Publication categoryResearch
Peer-reviewedYes