GADIS: Algorithm for designing sequences to achieve target secondary structure profiles of intrinsically disordered proteins
Harmon, Tyler S
Shammas, Sarah L
Posey, Ammon E
Pappu, Rohit V
Protein Engineering, Design & Selection
Oxford University Press
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Harmon, T. S., Crabtree, M., Shammas, S. L., Posey, A. E., Clarke, J., & Pappu, R. V. (2016). GADIS: Algorithm for designing sequences to achieve target secondary structure profiles of intrinsically disordered proteins. Protein Engineering, Design & Selection https://doi.org/10.1093/protein/gzw034
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 Genetic Algorithm for Design of Intrinsic secondary Structure (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.
design, GADIS, intrinsically disordered proteins, intrinsically helicity
The US-National Science Foundation and US-National Institutes of Health supported this work through grants MCB-1121867 and 5RO1 NS056114, respectively to R.V.P. J.C. and S.L.S. were supported by the Wellcome Trust (WT 095195MA). M.D.C. was supported by a Biotechnology and Biological Sciences Research Council (BBSRC) studentship.
Wellcome Trust (095195/Z/10/Z)
External DOI: https://doi.org/10.1093/protein/gzw034
This record's URL: https://www.repository.cam.ac.uk/handle/1810/257355