MIToS.jl: mutual information tools for protein sequence analysis in the Julia language

Parisi

et al. 2017

Preprint

Self Cite

CMB) ¶ These authors contributed equally to this work. AbstractConservation and covariation measures, as other evolutionary analysis, require a high number of distant homologous sequences, therefore a lot of structural divergence can be expected in such divergent alignments. However, most works linking evolutionary and structural information use a single structure ignoring the structural variability inside a protein family. That common practice seems unrealistic to the light of this work.In this work we studied how structural divergence affects conservation and covariation estimations. We uncover that, within a protein family, 51% of multiple sequence alignment columns change their exposed/buried status between structures. Also, 53% of residue pairs that are in contact in one structure are not in contact in another structure from the same family.We found out that residue conservation is not directly related to the relative solvent accessible surface area of a single protein structure. Using information from all the available structures rather than from a single representative structure gives more confidence in the structural interpretation of the evolutionary signals. That is particularly important for diverse multiple sequence alignments, where structures can drastically differ. High covariation scores tend to indicate residue contacts that are conserved in the family, therefore, are not suitable to find protein/conformer specific contacts.Our results suggest that structural divergence should be considered for a better understanding of protein function, to transfer annotation by homology and to model protein evolution.

Section: Covariation and Protein Contactsmentioning

confidence: 98%

Section: Data Set Constructionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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How is structural divergence related to evolutionary information?

Zea

Parisi

et al. 2017

Preprint

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“…Per-residue flexibility was estimated using the RSMF of the -carbons in the ensemble as calculated by MIToS 52 . RMSF values were normalized by dividing them by the protein average.…”

Section: Structural Information Of Protein Conformers and Ensemblesmentioning

confidence: 99%

Intrinsically disordered protein ensembles shape evolutionary rates revealing conformational patterns

Palopoli

Marchetti

et al. 2020

Preprint

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Intrinsically disordered proteins (IDPs) lack stable tertiary structure under physiological conditions. The unique composition and complex dynamical behaviour of IDPs make them a challenge for structural biology and molecular evolution studies. Using NMR ensembles, we found that IDPs evolve under a strong site-specific evolutionary rate heterogeneity, mainly originated by different constraints derived from their inter-residue contacts. Evolutionary rate profiles correlate with the experimentally observed conformational diversity of the protein, allowing the description of different conformational patterns possibly related to their structure-function relationships. The correlation between evolutionary rates and contact information improves when structural information is taken not from any individual conformer or the whole ensemble, but from combining a limited number of conformers. Our results suggest that residue contacts in disordered regions constrain evolutionary rates to conserve the dynamic behaviour of the ensemble and that evolutionary rates can be used as a proxy for the conformational diversity of IDPs.

“…Those works use the RASA and contact density of a single structure without taking into account the structural variability inside a protein family. This is even more extreme in the case of covariation scores, where inter-residue contacts are used to optimise their parameters and to assess the performance of the methods (Buslje et al, 2009;Jones et al, 2012;Zea et al, 2016), ignoring that residue contacts may vary between protein conformers and, even more, between different protein structures.…”

Section: Introductionmentioning

confidence: 99%

How is structural divergence related to evolutionary information?

Zea

Molecular Phylogenetics and Evolution

Parisi

et al. 2018

Self Cite

The analysis of evolutionary information in a protein family, such as conservation and covariation, is often linked to its structural information. Multiple sequence alignments of distant homologous sequences are used to measure evolutionary variables. Although high structural differences between proteins can be expected in such divergent alignments, most works linking evolutionary and structural information use a single structure ignoring the structural variability within protein families. The goal of this work is to elucidate the relevance of structural divergence when sequence-based measures are integrated with structural information. We found that inter-residue contacts and solvent accessibility undergo large variations in protein families. Our results show that high covariation scores tend to reveal residue contacts that are conserved in the family, instead of protein or conformer specific contacts. We also found that residue accessible surface area shows a high variability between structures of the same family. As a consequence, the mean relative solvent accessibility of multiple structures correlates better with the conservation pattern than the relative solvent accessibility of a single structure. We conclude that the use of comprehensive structural information allows a more accurate interpretation of the information computed from sequence alignments. Therefore, considering structural divergence would lead to a better understanding of protein function, dynamics, and evolution.