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  4. Statistical Analysis of Protein Sequences: A Coevolutionary Study of Molecular Chaperones
 
doctoral thesis

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

Malinverni, Duccio  
2018

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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Type
doctoral thesis
DOI
10.5075/epfl-thesis-8463
Author(s)
Malinverni, Duccio  
Advisors
De Los Rios, Paolo  
•
Barducci, Alessandro  
Jury

Prof. Paolo Ricci (président) ; Prof. Paolo De Los Rios, Dr Alessandro Barducci (directeurs) ; Prof. Matthieu Wyart, Dr Simona Cocco, Prof. Faruck Morcos (rapporteurs)

Date Issued

2018

Publisher

EPFL

Publisher place

Lausanne

Public defense year

2018-03-23

Thesis number

8463

Total of pages

123

Subjects

Correlated Mutations

•

Direct-Coupling Analysis

•

Statistical Inference

•

Probabilistic modeling

•

Molecular Chaperones

•

Hsp70

•

Iron-Sulfur Cluster Assembly

EPFL units
LBS  
Faculty
SB  
School
IPHYS  
Doctoral School
EDPY  
Available on Infoscience
March 15, 2018
Use this identifier to reference this record
https://infoscience.epfl.ch/handle/20.500.14299/145575
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