title: Structural basis of specific binding between Aurora A and TPX2 by molecular dynamics simulations.
abstract: 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.
authors.affiliation: Key Laboratory of Organic Optoelectronics and Molecular Engineering of Ministry of Education, Department of Chemistry, Tsinghua University, Beijing 100084, PR China.
authors.forename: Yuanhua
authors.initials: Y
authors.lastname: Cheng
authors.forename: Fushi
authors.initials: F
authors.lastname: Zhang
authors.forename: Quan
authors.initials: Q
authors.lastname: Chen
authors.forename: Jian
authors.initials: J
authors.lastname: Gao
authors.forename: Wei
authors.initials: W
authors.lastname: Cui
authors.forename: Mingjuan
authors.initials: M
authors.lastname: Ji
authors.forename: Chen-Ho
authors.initials: CH
authors.lastname: Tung
mesh_terms: D064127:Aurora Kinases; D018797:Cell Cycle Proteins / Q000737:chemistry* / Q000378:metabolism*; D008869:Microtubule-Associated Proteins / Q000737:chemistry* / Q000378:metabolism*; D056004:Molecular Dynamics Simulation; D009154:Mutation; D009687:Nuclear Proteins / Q000737:chemistry* / Q000378:metabolism*; D010455:Peptides / Q000494:pharmacology; D010750:Phosphoproteins / Q000737:chemistry* / Q000378:metabolism*; D011485:Protein Binding; D011487:Protein Conformation; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism*; D055550:Protein Stability; D013379:Substrate Specificity; D013816:Thermodynamics; D029867:Xenopus Proteins / Q000737:chemistry* / Q000378:metabolism*
chemical_list: D018797:Cell Cycle Proteins; D008869:Microtubule-Associated Proteins; D009687:Nuclear Proteins; D010455:Peptides; D010750:Phosphoproteins; D047428:Protein Kinase Inhibitors; C486551:TPX2 protein, Xenopus; D029867:Xenopus Proteins; D064127:Aurora Kinases; D017346:Protein Serine-Threonine Kinases