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.