The molecular mechanism behind protein kinase B natural mutant E17K affecting the allosteric inhibitor sensitivity: a molecular dynamics simulation study

Glu17Lys (E17K) is one of the natural variants of Akt1, which is associated with multiple human cancers. This mutation is also indicated to affect the sensitivity of certain allosteric inhibitors. In order to explain the molecular mechanism that E17K mutation of Akt1 affects the sensitivity of allosteric inhibitors, we performed molecular dynamics simulations on Akt1 to its allosteric inhibitors for both wild type and E17K. We analyzed the simulated data in terms of structural stability, hydrogen bond formation, pi-pi interactions, binding free energy etc. We found that E17K substitution will affect the interaction of K297 residues with allosteric inhibitors, which was a key residue in allosteric inhibitors binding. This will eventually lead to allosteric inhibitors leaving the binding site in the E17K system. Our results can provide a theoretical basis for the design of novel allosteric inhibitors targeting E17K mutants in the future.