title: GADIS: Algorithm for designing sequences to achieve target secondary structure profiles of intrinsically disordered proteins.
abstract: Many intrinsically disordered proteins (IDPs) participate in coupled folding and binding reactions and form alpha helical structures in their bound complexes. Alanine, glycine, or proline scanning mutagenesis approaches are often used to dissect the contributions of intrinsic helicities to coupled folding and binding. These experiments can yield confounding results because the mutagenesis strategy changes the amino acid compositions of IDPs. Therefore, an important next step in mutagenesis-based approaches to mechanistic studies of coupled folding and binding is the design of sequences that satisfy three major constraints. These are (i) achieving a target intrinsic alpha helicity profile; (ii) fixing the positions of residues corresponding to the binding interface; and (iii) maintaining the native amino acid composition. Here, we report the development of a G: enetic A: lgorithm for D: esign of I: ntrinsic secondary S: tructure (GADIS) for designing sequences that satisfy the specified constraints. We describe the algorithm and present results to demonstrate the applicability of GADIS by designing sequence variants of the intrinsically disordered PUMA system that undergoes coupled folding and binding to Mcl-1. Our sequence designs span a range of intrinsic helicity profiles. The predicted variations in sequence-encoded mean helicities are tested against experimental measurements.
authors: Department of Physics, Washington University in St. Louis, St. Louis, MO 63130, USA Department of Biomedical Engineering and Center for Biological Systems Engineering, Washington University in St. Louis, St. Louis, MO 63130, USA.
authors: Tyler S
authors: TS
authors: Harmon
authors: Department of Chemistry, University of Cambridge, Lensfield Road, CB2 1EW, Cambridge, UK.
authors: Michael D
authors: MD
authors: Crabtree
authors: Department of Chemistry, University of Cambridge, Lensfield Road, CB2 1EW, Cambridge, UK.
authors: Sarah L
authors: SL
authors: Shammas
authors: Department of Biomedical Engineering and Center for Biological Systems Engineering, Washington University in St. Louis, St. Louis, MO 63130, USA.
authors: Ammon E
authors: AE
authors: Posey
authors: Department of Chemistry, University of Cambridge, Lensfield Road, CB2 1EW, Cambridge, UK.
authors: Jane
authors: J
authors: Clarke
authors: Department of Biomedical Engineering and Center for Biological Systems Engineering, Washington University in St. Louis, St. Louis, MO 63130, USA pappu@wustl.edu.
authors: Rohit V
authors: RV
authors: Pappu
mesh_terms: D000465:Algorithms; D000595:Amino Acid Sequence; D064267:Intrinsically Disordered Proteins / Q000737:chemistry* / Q000235:genetics*; D008958:Models, Molecular; D016296:Mutagenesis; D015202:Protein Engineering / Q000379:methods*; D017433:Protein Structure, Secondary
chemical_list: D064267:Intrinsically Disordered Proteins
keywords: GADIS; design; intrinsically disordered proteins; intrinsically helicity