Journal
BIOINFORMATICS
Volume 35, Issue 15, Pages 2562-2568Publisher
OXFORD UNIV PRESS
DOI: 10.1093/bioinformatics/bty1031
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Funding
- Israel Science Foundation [802/16]
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Motivation Ancestral sequence reconstruction (ASR) is widely used to understand protein evolution, structure and function. Current ASR methodologies do not fully consider differences in evolutionary constraints among positions imposed by the three-dimensional (3D) structure of the protein. Here, we developed an ASR algorithm that allows different protein sites to evolve according to different mixtures of replacement matrices. We show that assigning replacement matrices to protein positions based on their solvent accessibility leads to ASR with higher log-likelihoods compared to naive models that assume a single replacement matrix for all sites. Improved ASR log-likelihoods are also demonstrated when solvent accessibility is predicted from protein sequences rather than inferred from a known 3D structure. Finally, we show that using such structure-aware mixture models results in substantial differences in the inferred ancestral sequences. Availability and implementation http://fastml.tau.ac.il. Supplementary information Supplementary data are available at Bioinformatics online.
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