Structural basis of specific binding between Aurora A and TPX2 by molecular dynamics simulations

In the present study, the impacts of G198N and W128F mutations on the recognition between Aurora A and targeting protein of Xenopus kinesin-like protein 2 (TPX2) were investigated using molecular dynamics (MD) simulations, free energy calculations, and free energy decomposition analysis. The predicted binding free energy of the wild-type complex is more favorable than those of three mutants, indicating that both single and double mutations are unfavorable for the Aurora A and TPX2 binding. It is also observed that the mutations alternate the binding pattern between Aurora A and TPX2, especially the downstream of TPX2. An intramolecular hydrogen bond between the atom OD of Asp11(TPX2) and the atom HE1 of Trp34(TPX2) disappear in three mutants and thus lead to the instability of the secondary structure of TPX2. The combination of different molecular modeling techniques is an efficient way to understand how mutation has impacts on the protein-protein binding and our work gives valuable information for the future design of specific peptide inhibitors for Aurora A.