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Abstract

In the present work, a polymer microfabricated microsprayer is characterised and tested for the mass spectrometric analysis of biomolecules, in particular in the context of protein mass spectrometry and proteomics. As the core of this work deals with analytical sciences and device development, Chapter 1 puts this work in perspective with the emergence of proteomics and more generally systems biology. In particular, major epistemological concepts that allowed the emergence of these new disciplines among life science research are reviewed. It is shown that the new paradigm of integrative biology did not emerge ex nihilo, but was preceded by major epistemological shifts in medicine, physics, and engineering. As such, the rise of systems biology appears as a new episode in the balance between reductionist and holistic approaches in the history of biology and medicine, and its biomedical promises are discussed. Chapter 2 reviews the state of the art in the hyphenation of microfluidic devices with electrospray mass spectrometry, both from a technical and applicative standpoint. Chapter 3 and 4 present the characterisation of the new polymer microspray for the analysis of peptides, proteins and glycoconjugates when coupled with various electrospray ion sources and instruments. In particular, a detailed comparison with classical pulled nanospray capillaries is performed, that established the performances in terms of sensitivity, stability and applicable ranges of flow rates and solvents. Chapter 5 introduces a functionalised polymer microspray for online sample clean-up. Basically, a hydrophobic polyvinylidene fluoride membrane is interfaced at the inlet of the polymer microspray to serve as a capture solid-phase of hydrophobic compounds; once captured, they can be cleaned up, and further eluted by the spray solution containing organic solvents. The process is further investigated in the presence of compounds usually used in protein sample preparation, such as chaotropes, reducing agents or detergents. Further microchip developments include the introduction of a dual channel microsprayer in Chapter 6, that allows to spray two solutions at the same time; given the microchip design, the two solutions are mixed only in the Taylor cone, where the electrospray is generated, and their respective flow rates can be controlled independently. This unique feature allows to analyse pure aqueous samples with integration of minimum amounts of organic sheath flow to promote desolvation and ionisation. Moreover, when proteins are analysed, it allows to measure them in their folded state, as demonstrated by their charge state distribution in the mass spectrum. Further tuning of the organic sheath flow allows to denature the protein within the Taylor cone, which can be monitored by the evolution of the protein charge state distribution in the mass spectrum. Potential of this technology for protein thermodynamic stability measurement is discussed. Lastly, Chapter 7 presents in silico evaluation of two technologies developed in the laboratory, namely Off-Gel electrophoresis for isoelectric fractionation of proteins and peptides mixtures, and online counting of cysteine residues within peptides during their analysis by electrospray mass spectrometry, to provide useful information to speed-up proteome profiling: if one wants to seek within a whole digested proteomes for peptides that are unique, measurement of their mass alone is hardly sufficient to perform useful protein identification, even with very high resolution, high mass accuracy instruments. The purpose of these simulations is to estimate how much information peptide isoelectric point and number of cysteines within each peptide provide in terms of number of unique peptides (and hence unambiguous peptide identification without MS/MS). Applicability of this strategy for high-throughput proteome profiling and its limitations are further discussed.

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