Phosphatidylinositol 3-kinase (PI3K) α is a heterodimeric lipid kinase that 
catalyzes the conversion of phosphoinositol-4,5-bisphosphate to 
phosphoinositol-3,4,5-trisphosphate. The PI3Kα signaling pathway plays an 
important role in cell growth, proliferation, and survival. This pathway is 
activated in numerous cancers, where the PI3KCA gene, which encodes for the 
p110α PI3Kα subunit, is mutated. Its mutation often results in gain of enzymatic 
activity; however, the mechanism of activation by oncogenic mutations remains 
unknown. Here, using computational methods, we show that oncogenic mutations 
that are far from the catalytic site and increase the enzymatic affinity 
destabilize the p110α-p85α dimer. By affecting the dynamics of the protein, 
these mutations favor the conformations that reduce the autoinhibitory effect of 
the p85α nSH2 domain. For example, we determined that, in all of the mutants, 
the nSH2 domain shows increased positional heterogeneity as compared with the 
wild-type, as demonstrated by changes in the fluctuation profiles computed by 
normal mode analysis of coarse-grained elastic network models. Analysis of the 
interdomain interactions of the wild-type and mutants at the p110α-p85α 
interface obtained with molecular dynamics simulations suggest that all of the 
tumor-associated mutations effectively weaken the interactions between p110α and 
p85α by disrupting key stabilizing interactions. These findings have important 
implications for understanding how oncogenic mutations change the conformational 
multiplicity of PI3Kα and lead to increased enzymatic activity. This mechanism 
may apply to other enzymes and/or macromolecular complexes that play a key role 
in cell signaling.