title: Understanding the folding-function tradeoff in proteins.
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.
authors.affiliation: National Centre for Biological Sciences, Tata Institute of Fundamental Research, Bangalore, India. shachi@ncbs.res.in
authors.forename: Shachi
authors.initials: S
authors.lastname: Gosavi
mesh_terms: D020816:Amino Acid Motifs; D000595:Amino Acid Sequence; D000596:Amino Acids / Q000378:metabolism; D001665:Binding Sites; D030562:Databases, Protein; D053583:Interleukin-1beta / Q000737:chemistry / Q000378:metabolism; D008840:Microfilament Proteins / Q000737:chemistry / Q000378:metabolism; D008958:Models, Molecular; D056004:Molecular Dynamics Simulation; D008969:Molecular Sequence Data; D017510:Protein Folding; D011506:Proteins / Q000737:chemistry* / Q000378:metabolism*; D015800:Protozoan Proteins / Q000737:chemistry / Q000378:metabolism
chemical_list: D000596:Amino Acids; D053583:Interleukin-1beta; D008840:Microfilament Proteins; D011506:Proteins; D015800:Protozoan Proteins; C058561:hisactophilin protein, Protozoan