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Homology Modeling in the Twilight Zone: Improved Accuracy by Sequence Space Analysis

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Homology Modeling

Part of the book series: Methods in Molecular Biology ((MIMB,volume 2627))

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Abstract

The analysis of the relationship between sequence and structure similarities during the evolution of a protein family has revealed a limit of sequence divergence for which structural conservation can be confidently assumed and homology modeling is reliable. Below this limit, the twilight zone corresponds to sequence divergence for which homology modeling becomes increasingly difficult and requires specific methods. Either with conventional threading methods or with recent deep learning methods, such as AlphaFold, the challenge relies on the identification of a template that shares not only a common ancestor (homology) but also a conserved structure with the query. As both homology and structural conservation are transitive properties, mining of sequence databases followed by multidimensional scaling (MDS) of the query sequence space can reveal intermediary sequences to infer homology and structural conservation between the query and the template. Here, as a case study, we studied the plethodontid receptivity factor isoform 1 (PRF1) from Plethodon jordani, a member of a pheromone protein family present only in lungless salamanders and weakly related to cytokines of the IL6 family. A variety of conventional threading methods led to the cytokine CNTF as a template. Sequence mining, followed by phylogenetic and MDS analysis, provided missing links between PRF1 and CNTF and allowed reliable homology modeling. In addition, we compared automated models obtained from web servers to a customized model to show how modeling can be improved by expert information.

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Acknowledgments

This study was supported by institutional grants from INSERM, CNRS, and University of Angers. MC is supported by CNRS. RB was supported by a fellowship from the University of Angers (France). AT was supported by a fellowship from the University of Carthage (Tunisia).

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  1. UMR CNRS 6015 – INSERM 1083, Laboratoire MITOVASC, Université d’Angers, Angers, France

    Rym Ben Boubaker, Asma Tiss, Daniel Henrion & Marie Chabbert

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  1. Rym Ben Boubaker
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  2. Asma Tiss
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Correspondence to Marie Chabbert .

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  1. Faculty of Chemistry, University of Warsaw, Warsaw, Poland

    Sławomir Filipek

1 Electronic Supplementary Material

Fig 1

Comparison of the customized and AlphaFold models. The customized MODELLER model (residues 10-187 of mature protién, white ribbon) is superimposed with the AlphaFold model deposited in UniProt (AF_Q9PUJ2-F1, slate) and the CNTF template (PDB access number: 1CNT, magenta). Phe-70 of PRF1 and Trp-64 of CNTF are shown as sticks. (ZIP 1.67MB)

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Ben Boubaker, R., Tiss, A., Henrion, D., Chabbert, M. (2023). Homology Modeling in the Twilight Zone: Improved Accuracy by Sequence Space Analysis. In: Filipek, S. (eds) Homology Modeling. Methods in Molecular Biology, vol 2627. Humana, New York, NY. https://doi.org/10.1007/978-1-0716-2974-1_1

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  • DOI: https://doi.org/10.1007/978-1-0716-2974-1_1

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  • Publisher Name: Humana, New York, NY

  • Print ISBN: 978-1-0716-2973-4

  • Online ISBN: 978-1-0716-2974-1

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