Understanding the folding-function tradeoff in proteins

PLoS One. 2013 Apr 12;8(4):e61222. doi: 10.1371/journal.pone.0061222. Print 2013.

Abstract

When an amino-acid sequence cannot be optimized for both folding and function, folding can get compromised in favor of function. To understand this tradeoff better, we devise a novel method for extracting the "function-less" folding-motif of a protein fold from a set of structurally similar but functionally diverse proteins. We then obtain the β-trefoil folding-motif, and study its folding using structure-based models and molecular dynamics simulations. CompariA protein sequence serves two purpson with the folding of wild-type β-trefoil proteins shows that function affects folding in two ways: In the slower folding interleukin-1β, binding sites make the fold more complex, increase contact order and slow folding. In the faster folding hisactophilin, residues which could have been part of the folding-motif are used for function. This reduces the density of native contacts in functional regions and increases folding rate. The folding-motif helps identify subtle structural deviations which perturb folding. These may then be used for functional annotation. Further, the folding-motif could potentially be used as a first step in the sequence design of function-less scaffold proteins. Desired function can then be engineered into these scaffolds.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amino Acid Motifs
  • Amino Acid Sequence
  • Amino Acids / metabolism
  • Binding Sites
  • Databases, Protein
  • Interleukin-1beta / chemistry
  • Interleukin-1beta / metabolism
  • Microfilament Proteins / chemistry
  • Microfilament Proteins / metabolism
  • Models, Molecular
  • Molecular Dynamics Simulation
  • Molecular Sequence Data
  • Protein Folding*
  • Proteins / chemistry*
  • Proteins / metabolism*
  • Protozoan Proteins / chemistry
  • Protozoan Proteins / metabolism

Substances

  • Amino Acids
  • Interleukin-1beta
  • Microfilament Proteins
  • Proteins
  • Protozoan Proteins
  • hisactophilin protein, Protozoan

Grants and funding

SG was supported by core funding from the Government of India-DAE and the Govt of India-DST-Ramanujan Fellowship (SR/S2/RJN-63/2009, 5 years, wef 29/06/2010). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.