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Evolutionary model of protein secondary structure capable of revealing new biological relationships

By Jhih-Siang Lai, Burkhard Rost, Bostjan Kobe, Mikael Boden

Posted 28 Feb 2019
bioRxiv DOI: 10.1101/563452 (published DOI: 10.1002/prot.25898)

Ancestral sequence reconstruction has had recent success in decoding the origins and the determinants of complex protein functions. However, phylogenetic analyses of remote homologues must handle extreme amino-acid sequence diversity resulting from extended periods of evolutionary change. We exploited the wealth of protein structures to develop an evolutionary model based on protein secondary structure. The approach follows the differences between discrete secondary structure states observed in modern proteins and those hypothesised in their immediate ancestors. We implemented maximum likelihood-based phylogenetic inference to reconstruct ancestral secondary structure. The predictive accuracy from the use of the evolutionary model surpasses that of comparative modelling and sequence-based prediction; the reconstruction extracts information not available from modern structures or the ancestral sequences alone. Based on a phylogenetic analysis of multiple protein families, we showed that the model can highlight relationships that are evolutionarily rooted in structure and not evident in amino acid-based analysis.

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