Structural insights into Phosphoinositide 3-kinase (PI3K) regulation using molecular dynamics simulations

Diplôme Master Structural insights into Phosphoinositide 3-kinase (PI3K) regulation using molecular dynamics simulations eng 2015 author Patmanidis Ilias 806737 director Scapozza Leonardo 600318 director Lisacek Frédérique 0000-0002-0948-4537 639315 director Chiriano Gianpaolo 784524 director Vadas Oscar 508966 Phosphoinositide 3-kinases (PI3Ks) are lipid kinases phosphorylating the 3' inositol ring of inositol-phospholipids (PtdIns) which ultimately regulate key cellular functions. We focused on the α isoform of class I PI3Ks and different mutants (G106V, N345K, E545K and H1047R), which are associated with different types of cancer. The main goal of this work is to understand the dynamics of these enzymes by conducting computational studies and explain in atomistic details the experimental results reported in literature. A better understanding of the molecular mechanisms of the PI3Kα isoform's oncogenic potential is extremely relevant towards a clearer elucidation of its biology and the designing of new effective therapeutics. Our results demonstrate that mutations on the interacting surface between the catalytic and the regulatory subunit destabilize the enzyme, weaken key interactions among its domains and ultimately affect its regulation and activation. Computational approaches are able to produce results in agreement with experimental studies and with this work we provide a framework for the preparation, analysis and interpretation of these results. Dewey 570 Dewey 615 Bioinformatics and data analysis in biology (BIADB) 30 Section de biologie 16 31 Section des sciences pharmaceutiques 17 false 5b65b472-a261-4183-a668-99b615e61e57 Master thesis Restricted Ilias_Patmanidis_Master_thesis.pdf 8158497 application/pdf restrictedAccess Faculté des sciences / Section de biologie Faculté des sciences / Section des sciences pharmaceutiques

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Structural insights into Phosphoinositide 3-kinase (PI3K) regulation using molecular dynamics simulations				2015	275	51

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Patmanidis, Ilias