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High-Throughput Reconstruction of Ancestral Protein Sequence, Structure, and Molecular Function

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Computational Methods in Protein Evolution

Part of the book series: Methods in Molecular Biology ((MIMB,volume 1851))

Abstract

Ancestral protein sequence reconstruction is a powerful technique for explicitly testing hypotheses about the evolution of molecular function, allowing researchers to meticulously dissect how historical changes in protein sequence impacted functional repertoire by altering the protein’s 3D structure. These techniques have provided concrete, experimentally validated insights into ancient evolutionary processes and help illuminate the complex relationship between protein sequence, structure, and function. Inferring the protein family phylogenies on which ancestral sequence reconstruction depends and reconstructing the sequences, themselves, are amenable to high-throughput computational analysis. However, determining the structures of ancestral-reconstructed proteins and characterizing their functions typically rely on time-consuming and expensive laboratory analyses, limiting most current studies to examining a relatively small number of specific hypotheses. For this reason, we have little detailed, unbiased information about how molecular function evolves across large protein family phylogenies. Here we describe a generalized protocol that integrates ancestral sequence reconstruction with structural homology modeling and structure-based molecular affinity prediction to characterize historical changes in protein function across families with thousands of individual sequences. We highlight key steps in the analysis protocol requiring particularly careful attention to avoid introducing potential errors as well as steps for which computationally efficient subroutines can be substituted for more intensive approaches, allowing researchers to scale the analysis up or down, depending on available resources and requirements for reproducibility and scientific rigor. In our view, this approach provides a compelling compliment to more laboratory-intensive procedures, generating important contextual information that can help guide detailed experiments.

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Notes

  1. 1.

    The Python scripts described in this chapter are hosted with the online version of the book.

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Author information

Authors and Affiliations

  1. Department of Microbiology & Cell Science, Institute for Food and Agricultural Sciences, University of Florida, Gainesville, FL, USA

    Kelsey Aadland, Charles Pugh & Bryan Kolaczkowski

  2. Genetics Institute, University of Florida, Gainesville, FL, USA

    Bryan Kolaczkowski

Authors
  1. Kelsey Aadland
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  2. Charles Pugh
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  3. Bryan Kolaczkowski
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Correspondence to Bryan Kolaczkowski .

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Editors and Affiliations

  1. GlaxoSmithKline, Cellzome – a GSK company Meyerhofstrasse 1, Heidelberg, Baden-Württemberg, Germany

    Tobias Sikosek

1 Electronic Supplementary Material

Data 1

Python scripts and data required for the presented examples. (ZIP 10 KB)

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Aadland, K., Pugh, C., Kolaczkowski, B. (2019). High-Throughput Reconstruction of Ancestral Protein Sequence, Structure, and Molecular Function. In: Sikosek, T. (eds) Computational Methods in Protein Evolution. Methods in Molecular Biology, vol 1851. Humana Press, New York, NY. https://doi.org/10.1007/978-1-4939-8736-8_8

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  • DOI: https://doi.org/10.1007/978-1-4939-8736-8_8

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  • Publisher Name: Humana Press, New York, NY

  • Print ISBN: 978-1-4939-8735-1

  • Online ISBN: 978-1-4939-8736-8

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