MD simulations of L551Q as a novel carcinogenic PI3Kα mutation

Introduction & Objectives: the p110α subunit of PI3K class IA enzymes is encoded by PIK3CA in which take place a huge number of mutations associated with breast cancer. Here, the mutations in exon 9 of PIK3CA was probed and computationally simulate their function was performed.Material & Methods: mutation detection in 40 breast cancer specimens was done by PCR/HRM and PCR/sequencing. The identified mutations were queried via in silico algorithms to check the pathogenicity. The molecular dynamics (MD) simulations were utilized to assess the function of mutant proteins.Results: Three samples were found to harbor at least one of the E542K, E545K and L551Q mutations of which L551Q has not been reported previously. All mutations were confirmed to be pathogenic and MD simulations revealed their impact on protein function and regulation. The novel L551Q mutant dynamics was similar to that of previously found carcinogenic mutants, E542K and E545K. A functional role for the helical domain was also suggested by which the inhibitory signal of p85α is conducted to kinase domain via helical domain. Helical domain mutations lead to impairment of kinase domain allosteric regulation. Interestingly, our results show that p110α substrate binding pocket of kinase domain in mutants may have differential affinity for enzyme substrates, including anit-p110α drugs.Conclusions The novel p110α L551Q mutation could be considered as carcinogenic mutation similar to previously known mutations (E542K and E545K).