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Local versus global fold switching in protein evolution: insight from a three-letter continuous model.

Holzgräfe, Christian LU and Wallin, Stefan LU (2015) In Physical Biology 12(2).
Abstract
Recent design experiments have demonstrated that some proteins can switch their folds in response to a small number of point mutations either directly, in a single mutational step, or via intermediate bistable sequences, which populate two different folds simultaneously. Here we explore the hypothesis that bistable intermediates are more common in switches between structurally similar folds while direct switches are more common between dissimilar folds. To this end, we use a reduced model with seven atoms per amino acid and three amino acid types as a biophysical basis for protein folding and stability. We compare a set of mutational pathways, selected for optimal stability properties, that lead to switches between β-hairpin and α-helix... (More)
Recent design experiments have demonstrated that some proteins can switch their folds in response to a small number of point mutations either directly, in a single mutational step, or via intermediate bistable sequences, which populate two different folds simultaneously. Here we explore the hypothesis that bistable intermediates are more common in switches between structurally similar folds while direct switches are more common between dissimilar folds. To this end, we use a reduced model with seven atoms per amino acid and three amino acid types as a biophysical basis for protein folding and stability. We compare a set of mutational pathways, selected for optimal stability properties, that lead to switches between β-hairpin and α-helix folds with 16 amino acids and between [Formula: see text] and [Formula: see text] folds with 35 amino acids, respectively. Fold switching in each case is sharp, taking only a few mutations to be completed. While the sharpness of mutationally driven protein fold switching can be traced to a shift in the energy balance of the two native states, conformational entropy contributes to determining the point at which fold switching occurs along a pathway. (Less)
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author
organization
publishing date
type
Contribution to journal
publication status
published
subject
in
Physical Biology
volume
12
issue
2
publisher
IOP Publishing
external identifiers
  • pmid:25706822
  • wos:000357203400005
  • scopus:84928798137
ISSN
1478-3975
DOI
10.1088/1478-3975/12/2/026002
language
English
LU publication?
yes
id
5d21c742-596a-48fc-ac4e-3f36b65a5eff (old id 5143001)
date added to LUP
2015-04-10 15:24:41
date last changed
2017-10-01 03:25:28
@article{5d21c742-596a-48fc-ac4e-3f36b65a5eff,
  abstract     = {Recent design experiments have demonstrated that some proteins can switch their folds in response to a small number of point mutations either directly, in a single mutational step, or via intermediate bistable sequences, which populate two different folds simultaneously. Here we explore the hypothesis that bistable intermediates are more common in switches between structurally similar folds while direct switches are more common between dissimilar folds. To this end, we use a reduced model with seven atoms per amino acid and three amino acid types as a biophysical basis for protein folding and stability. We compare a set of mutational pathways, selected for optimal stability properties, that lead to switches between β-hairpin and α-helix folds with 16 amino acids and between [Formula: see text] and [Formula: see text] folds with 35 amino acids, respectively. Fold switching in each case is sharp, taking only a few mutations to be completed. While the sharpness of mutationally driven protein fold switching can be traced to a shift in the energy balance of the two native states, conformational entropy contributes to determining the point at which fold switching occurs along a pathway.},
  articleno    = {026002},
  author       = {Holzgräfe, Christian and Wallin, Stefan},
  issn         = {1478-3975},
  language     = {eng},
  number       = {2},
  publisher    = {IOP Publishing},
  series       = {Physical Biology},
  title        = {Local versus global fold switching in protein evolution: insight from a three-letter continuous model.},
  url          = {http://dx.doi.org/10.1088/1478-3975/12/2/026002},
  volume       = {12},
  year         = {2015},
}