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Design of Protein Multi-specificity Using an Independent Sequence Search Reduces the Barrier to Low Energy Sequences

Author

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  • Alexander M Sevy
  • Tim M Jacobs
  • James E Crowe Jr.
  • Jens Meiler

Abstract

Computational protein design has found great success in engineering proteins for thermodynamic stability, binding specificity, or enzymatic activity in a ‘single state’ design (SSD) paradigm. Multi-specificity design (MSD), on the other hand, involves considering the stability of multiple protein states simultaneously. We have developed a novel MSD algorithm, which we refer to as REstrained CONvergence in multi-specificity design (RECON). The algorithm allows each state to adopt its own sequence throughout the design process rather than enforcing a single sequence on all states. Convergence to a single sequence is encouraged through an incrementally increasing convergence restraint for corresponding positions. Compared to MSD algorithms that enforce (constrain) an identical sequence on all states the energy landscape is simplified, which accelerates the search drastically. As a result, RECON can readily be used in simulations with a flexible protein backbone. We have benchmarked RECON on two design tasks. First, we designed antibodies derived from a common germline gene against their diverse targets to assess recovery of the germline, polyspecific sequence. Second, we design “promiscuous”, polyspecific proteins against all binding partners and measure recovery of the native sequence. We show that RECON is able to efficiently recover native-like, biologically relevant sequences in this diverse set of protein complexes.Author Summary: The ability to design a new protein with a desired activity has been a longstanding goal of computational biologists, to create proteins with new binding activity or increased stability. An even more ambitious goal is multi-specificity design, which extends general protein design by creating a sequence that has low energy with multiple binding partners. We have developed a new algorithm for multi-specificity design that more efficiently finds a low energy sequence for all complexes. This increased efficiency enables simulation of biologically relevant motion between binding partners, such as backbone movement and shifts in orientation. We show that our algorithm outperforms existing approaches, and compare the predicted low energy sequences to the sequences naturally seen through evolution of each protein. We find that this algorithm is able to more accurately represent the scope of sequences that are found in biological contexts. This method can be applied to design new proteins with the ability to bind multiple distinct partners.

Suggested Citation

  • 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.
  • Handle: RePEc:plo:pcbi00:1004300
    DOI: 10.1371/journal.pcbi.1004300
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    References listed on IDEAS

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    1. Andrew Leaver-Fay & Ron Jacak & P Benjamin Stranges & Brian Kuhlman, 2011. "A Generic Program for Multistate Protein Design," PLOS ONE, Public Library of Science, vol. 6(7), pages 1-17, July.
    2. 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.
    3. Jordan R Willis & Bryan S Briney & Samuel L DeLuca & James E Crowe Jr & Jens Meiler, 2013. "Human Germline Antibody Gene Segments Encode Polyspecific Antibodies," PLOS Computational Biology, Public Library of Science, vol. 9(4), pages 1-14, April.
    4. Gevorg Grigoryan & Aaron W. Reinke & Amy E. Keating, 2009. "Design of protein-interaction specificity gives selective bZIP-binding peptides," Nature, Nature, vol. 458(7240), pages 859-864, April.
    5. 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.
    6. Sarel J Fleishman & Andrew Leaver-Fay & Jacob E Corn & Eva-Maria Strauch & Sagar D Khare & Nobuyasu Koga & Justin Ashworth & Paul Murphy & Florian Richter & Gordon Lemmon & Jens Meiler & David Baker, 2011. "RosettaScripts: A Scripting Language Interface to the Rosetta Macromolecular Modeling Suite," PLOS ONE, Public Library of Science, vol. 6(6), pages 1-10, June.
    7. Justin Ashworth & James J. Havranek & Carlos M. Duarte & Django Sussman & Raymond J. Monnat & Barry L. Stoddard & David Baker, 2006. "Computational redesign of endonuclease DNA binding and cleavage specificity," Nature, Nature, vol. 441(7093), pages 656-659, June.
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    1. Patrick Löffler & Samuel Schmitz & Enrico Hupfeld & Reinhard Sterner & Rainer Merkl, 2017. "Rosetta:MSF: a modular framework for multi-state computational protein design," PLOS Computational Biology, Public Library of Science, vol. 13(6), pages 1-24, June.
    2. Steven Schulz & Sébastien Boyer & Matteo Smerlak & Simona Cocco & Rémi Monasson & Clément Nizak & Olivier Rivoire, 2021. "Parameters and determinants of responses to selection in antibody libraries," PLOS Computational Biology, Public Library of Science, vol. 17(3), pages 1-24, March.
    3. Alexander M Sevy & Swetasudha Panda & James E Crowe Jr & Jens Meiler & Yevgeniy Vorobeychik, 2018. "Integrating linear optimization with structural modeling to increase HIV neutralization breadth," PLOS Computational Biology, Public Library of Science, vol. 14(2), pages 1-18, February.

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