Abstract
PI3Kα is a heterodimer protein consisting of two subunits (p110α and p85α) which promotes various signaling pathways. Oncogenic mutation in the catalytic subunit p110α of PI3Kα at the 1047 position in the kinase domain substitutes the histidine with arginine. This mutation brings about conformational transitions in the protein complex. These transitions expose the membrane binding region of PI3Kα, and then it independently binds to the cell membrane through its kinase domain without the involvement of the membrane-bound protein RAS. We observed notable changes between the protein complexes (p110α-p85α) of native and mutant structures at the atomic level using molecular dynamics simulations. Simulation results revealed formation of a less number of hydrogen bonds between the two subunits in the mutant protein complex which led the two subunits to move away from each other. This increase in distance between the subunits led to an expanded structure, thereby increasing the flexibility of the protein complex. Furthermore, a study of secondary structure elements and the electrostatic potential of the protein also gave a molecular insight into the change in interaction patterns of the protein with the plasma membrane. Our finding clearly indicates the role of mutation in oncogenesis and provides an insight into considering the structural aspects to handle this mutation.