Publication

Statistical Analysis of Protein Sequences: A Coevolutionary Study of Molecular Chaperones

Duccio Malinverni
2018
EPFL thesis
Abstract

Recent advances in DNA sequencing technologies led to the accumulation of enormous quantities of genetic information available in public databases. This rapid growth of available biological datasets calls for quantitative analysis tools and concomitantly opens the doors for new analysis paradigms. Particularly, the analysis of correlated mutations and their structural interpretation have witnessed a second youth in the last years. A natural formulation for such approaches is provided by the statistical physics of disordered systems. This thesis is articulated around different projects aimed at studying particular biological systems of interests, the Hsp70 molecular chaperones, through the lens provided by methods rooted in statistical physics. In a first project, we focus on correlated mutations within the Hsp70 family. Our analysis reveals the existence of a biologically important macro-molecular arrangement of these chaperones and we investigate its phylogenetic origin. A second project investigates the interactions between the Hsp70 chaperones and one of their main co-chaperones, J-proteins. Through the combined use of coevolutionary analysis and molecular simulations at both coarse-grained and atomistic levels, we construct a structural and dynamical model of this interaction which rationalizes previous experimental evidence. In a subsequent study, we specifically focus on the J-protein co-chaperones. Through phylogenetic and coevolutionary methods, we investigate the origin of recently discovered interactions which form the basis of the disaggregation machinery in higher eukaryotes. Finally, in a fourth project, we shift our attention to the analysis of proteins involved in the iron-sulfur cluster assembly pathway. Analysis of residue coevolution in the different proteins composing this pathway reveals multiple structural insights at several scales.

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Related concepts (35)
Chaperone (protein)
In molecular biology, molecular chaperones are proteins that assist the conformational folding or unfolding of large proteins or macromolecular protein complexes. There are a number of classes of molecular chaperones, all of which function to assist large proteins in proper protein folding during or after synthesis, and after partial denaturation. Chaperones are also involved in the translocation of proteins for proteolysis. The first molecular chaperones discovered were a type of assembly chaperones which assist in the assembly of nucleosomes from folded histones and DNA.
Protein folding
Protein folding is the physical process where a protein chain is translated into its native three-dimensional structure, typically a "folded" conformation, by which the protein becomes biologically functional. Via an expeditious and reproducible process, a polypeptide folds into its characteristic three-dimensional structure from a random coil. Each protein exists first as an unfolded polypeptide or random coil after being translated from a sequence of mRNA into a linear chain of amino acids.
Protein
Proteins are large biomolecules and macromolecules that comprise one or more long chains of amino acid residues. Proteins perform a vast array of functions within organisms, including catalysing metabolic reactions, DNA replication, responding to stimuli, providing structure to cells and organisms, and transporting molecules from one location to another. Proteins differ from one another primarily in their sequence of amino acids, which is dictated by the nucleotide sequence of their genes, and which usually results in protein folding into a specific 3D structure that determines its activity.
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