RESUMO
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.
Assuntos
Proteínas Intrinsicamente Desordenadas/química , Modelos Moleculares , Conformação Proteica , Aminoácidos , Sítios de Ligação , Evolução Molecular , Humanos , Proteínas Intrinsicamente Desordenadas/genética , Proteínas Intrinsicamente Desordenadas/metabolismo , Ressonância Magnética Nuclear Biomolecular , Ligação Proteica , Relação Estrutura-AtividadeRESUMO
The Student Council of the International Society for Computational Biology (ISCB-SC) is a student-focused organization for researchers from all early career levels of training (undergraduates, masters, PhDs and postdocs) that organizes bioinformatics and computational biology activities across the globe. Among its activities, the ISCB-SC organizes several symposia in different continents, many times, with the help of the Regional Student Groups (RSGs) that are based on each region. In this editorial we highlight various key moments and learned lessons from the 14th Student Council Symposium (SCS, Chicago, USA), the 5th European Student Council Symposium (ESCS, Athens, Greece) and the 3rd Latin American Student Council Symposium (LA-SCS, Viña del Mar, Chile).
Assuntos
Biologia Computacional , Liderança , Estudantes , Chile , Humanos , PesquisadoresRESUMO
Conformational diversity of the native state plays a central role in modulating protein function. The selection paradigm sustains that different ligands shift the conformational equilibrium through their binding to highest-affinity conformers. Intramolecular vibrational dynamics associated to each conformation should guarantee conformational transitions, which due to its importance, could possibly be associated with evolutionary conserved traits. Normal mode analysis, based on a coarse-grained model of the protein, can provide the required information to explore these features. Herein, we present a novel procedure to identify key positions sustaining the conformational diversity associated to ligand binding. The method is applied to an adequate refined dataset of 188 paired protein structures in their bound and unbound forms. Firstly, normal modes most involved in the conformational change are selected according to their corresponding overlap with structural distortions introduced by ligand binding. The subspace defined by these modes is used to analyze the effect of simulated point mutations on preserving the conformational diversity of the protein. We find a negative correlation between the effects of mutations on these normal mode subspaces associated to ligand-binding and position-specific evolutionary conservations obtained from multiple sequence-structure alignments. Positions whose mutations are found to alter the most these subspaces are defined as key positions, that is, dynamically important residues that mediate the ligand-binding conformational change. These positions are shown to be evolutionary conserved, mostly buried aliphatic residues localized in regular structural regions of the protein like ß-sheets and α-helix.