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Predicting the Tolerated Sequences for Proteins and Protein Interfaces Using RosettaBackrub Flexible Backbone Design

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  • Colin A Smith
  • Tanja Kortemme

Abstract

Predicting the set of sequences that are tolerated by a protein or protein interface, while maintaining a desired function, is useful for characterizing protein interaction specificity and for computationally designing sequence libraries to engineer proteins with new functions. Here we provide a general method, a detailed set of protocols, and several benchmarks and analyses for estimating tolerated sequences using flexible backbone protein design implemented in the Rosetta molecular modeling software suite. The input to the method is at least one experimentally determined three-dimensional protein structure or high-quality model. The starting structure(s) are expanded or refined into a conformational ensemble using Monte Carlo simulations consisting of backrub backbone and side chain moves in Rosetta. The method then uses a combination of simulated annealing and genetic algorithm optimization methods to enrich for low-energy sequences for the individual members of the ensemble. To emphasize certain functional requirements (e.g. forming a binding interface), interactions between and within parts of the structure (e.g. domains) can be reweighted in the scoring function. Results from each backbone structure are merged together to create a single estimate for the tolerated sequence space. We provide an extensive description of the protocol and its parameters, all source code, example analysis scripts and three tests applying this method to finding sequences predicted to stabilize proteins or protein interfaces. The generality of this method makes many other applications possible, for example stabilizing interactions with small molecules, DNA, or RNA. Through the use of within-domain reweighting and/or multistate design, it may also be possible to use this method to find sequences that stabilize particular protein conformations or binding interactions over others.

Suggested Citation

  • Colin A Smith & Tanja Kortemme, 2011. "Predicting the Tolerated Sequences for Proteins and Protein Interfaces Using RosettaBackrub Flexible Backbone Design," PLOS ONE, Public Library of Science, vol. 6(7), pages 1-11, July.
  • Handle: RePEc:plo:pone00:0020451
    DOI: 10.1371/journal.pone.0020451
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    References listed on IDEAS

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    1. Gregory D Friedland & Nils-Alexander Lakomek & Christian Griesinger & Jens Meiler & Tanja Kortemme, 2009. "A Correspondence Between Solution-State Dynamics of an Individual Protein and the Sequence and Conformational Diversity of its Family," PLOS Computational Biology, Public Library of Science, vol. 5(5), pages 1-16, May.
    2. Elisabeth L Humphris & Tanja Kortemme, 2007. "Design of Multi-Specificity in Protein Interfaces," PLOS Computational Biology, Public Library of Science, vol. 3(8), pages 1-14, August.
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    Cited by:

    1. Alexander M Sevy & Tim M Jacobs & James E Crowe Jr. & Jens Meiler, 2015. "Design of Protein Multi-specificity Using an Independent Sequence Search Reduces the Barrier to Low Energy Sequences," PLOS Computational Biology, Public Library of Science, vol. 11(7), pages 1-23, July.
    2. Aliza B Rubenstein & Manasi A Pethe & Sagar D Khare, 2017. "MFPred: Rapid and accurate prediction of protein-peptide recognition multispecificity using self-consistent mean field theory," PLOS Computational Biology, Public Library of Science, vol. 13(6), pages 1-24, June.

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