Phosphoinositide 3-kinase alpha (PI3Kα) is involved in fundamental cellular processes including cell proliferation and differentiation and is frequently mutated in human malignancies. One of the most common mutations is E545K, which results in an amino acid substitution of opposite charge. It has been recently proposed that in this oncogenic charge-reversal mutation, the interactions between the protein catalytic and regulatory subunits are abrogated, resulting in loss of regulation and constitutive PI3Kα activity, which can lead to oncogenesis. To assess the mechanism of the PI3Kα E545K activating mutation, extensive MD simulations were performed to examine conformational changes differing between the wild type (WT) and mutant proteins as they occur in microsecond simulations. In the mutant protein form, we observe a spontaneous detachment of the nSH2 PI3Kα domain (regulatory subunit, p85α) from the helical domain (catalytic subunit, p110α), which results in significant loss of communication between the regulatory and catalytic subunits. We examine the allosteric network of the two proteins and show that a cluster of residues around the mutation is important in delivering communication signals between the catalytic and regulatory subunits. Our results demonstrate the dynamical and structural differences that occur upon the p110α E545K mutation in atomic level detail and indicate a possible mechanism for the loss of regulation that E545K confers on PI3Kα. The full energy landscape is then further studied using Metadynamics calculations. These results have been further exploited to discover mutant-selective PI3Kα inhibitors.<sup>1</sup><br/><br/>

Insights into the mechanism of the PIK3CA E545K activating mutation using MD simulations

2019 Spring National Meeting

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