Detection and sequence/structure mapping of biophysical constraints to protein variation in saturated mutational libraries and protein sequence alignments with a dedicated server

BMC Bioinformatics

Research Article

Luciano A. Abriata¹  Matteo Dal Peraro¹  Christophe Bovigny² 

[1] Laboratory for Biomolecular Modeling, Institute of Bioengineering, School of Life Sciences, École Polytechnique Fédérale de Lausanne, and Swiss Institute of Bioinformatics, AAB014 Station 19, 1015, Lausanne, Switzerland;Laboratory for Biomolecular Modeling, Institute of Bioengineering, School of Life Sciences, École Polytechnique Fédérale de Lausanne, and Swiss Institute of Bioinformatics, AAB014 Station 19, 1015, Lausanne, Switzerland;Present address: Molecular Modeling Group, Swiss Institute of Bioinformatics, UNIL, Bâtiment Génopode, 1015, Lausanne, Switzerland;

关键词: Deep sequencing;    Next-generation sequencing;    High-throughput;    Protein evolution;    Protein design;    structure-function relationships;    Protein biophysics;    Structural biology;    Neutral drift;   

DOI  :  10.1186/s12859-016-1124-4

 received in 2016-03-01, accepted in 2016-06-07,  发布年份 2016

来源: Springer

【 摘 要 】

BackgroundProtein variability can now be studied by measuring high-resolution tolerance-to-substitution maps and fitness landscapes in saturated mutational libraries. But these rich and expensive datasets are typically interpreted coarsely, restricting detailed analyses to positions of extremely high or low variability or dubbed important beforehand based on existing knowledge about active sites, interaction surfaces, (de)stabilizing mutations, etc.ResultsOur new webserver PsychoProt (freely available without registration at http://psychoprot.epfl.ch or at http://lucianoabriata.altervista.org/psychoprot/index.html) helps to detect, quantify, and sequence/structure map the biophysical and biochemical traits that shape amino acid preferences throughout a protein as determined by deep-sequencing of saturated mutational libraries or from large alignments of naturally occurring variants.DiscussionWe exemplify how PsychoProt helps to (i) unveil protein structure-function relationships from experiments and from alignments that are consistent with structures according to coevolution analysis, (ii) recall global information about structural and functional features and identify hitherto unknown constraints to variation in alignments, and (iii) point at different sources of variation among related experimental datasets or between experimental and alignment-based data. Remarkably, metabolic costs of the amino acids pose strong constraints to variability at protein surfaces in nature but not in the laboratory. This and other differences call for caution when extrapolating results from in vitro experiments to natural scenarios in, for example, studies of protein evolution.ConclusionWe show through examples how PsychoProt can be a useful tool for the broad communities of structural biology and molecular evolution, particularly for studies about protein modeling, evolution and design.

【 授权许可】

CC BY   
© The Author(s). 2016