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

Holzgräfe, Christian LU and Wallin, Stefan LU (2014) In Biophysical Journal 107(5). p.1217-1225
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... (More)
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. (Less)
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author
organization
publishing date
type
Contribution to journal
publication status
published
subject
in
Biophysical Journal
volume
107
issue
5
pages
1217 - 1225
publisher
Cell Press
external identifiers
  • pmid:25185557
  • wos:000341275100022
  • scopus:84928787542
ISSN
1542-0086
DOI
10.1016/j.bpj.2014.07.020
language
English
LU publication?
yes
id
b297a1f6-6611-4d50-b19d-a5d13496a6c0 (old id 4692423)
date added to LUP
2014-10-03 13:59:54
date last changed
2017-10-01 03:05:48
@article{b297a1f6-6611-4d50-b19d-a5d13496a6c0,
  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.},
  author       = {Holzgräfe, Christian and Wallin, Stefan},
  issn         = {1542-0086},
  language     = {eng},
  number       = {5},
  pages        = {1217--1225},
  publisher    = {Cell Press},
  series       = {Biophysical Journal},
  title        = {Smooth Functional Transition along a Mutational Pathway with an Abrupt Protein Fold Switch.},
  url          = {http://dx.doi.org/10.1016/j.bpj.2014.07.020},
  volume       = {107},
  year         = {2014},
}