Peptide probes derived from pertuzumab by molecular dynamics modeling for HER2 positive tumor imaging

Journal article

A high level of HER2 expression in breast cancer correlates with a higher tumor growth rate, high metastatic potential, and a poor long-term patient survival rate. Pertuzumab, a human monoclonal antibody, can reduce the effect of HER2 overexpression by preventing HER2 dimerization. In this study, a combination protocol of molecular dynamics modeling and MM/GBSA binding free energy calculations was applied to design peptides that interact with HER2 based on the HER2/pertuzumab crystal structure. Based on a β hairpin in pertuzumab from Glu46 to Lys65-which plays a key role in interacting with HER2-mutations were carried out in silico to improve the binding free energy of the hairpin that interacts with the Phe256-Lys314 of the HER2 protein. Combined the use of one-bead-one-compound library screening, among all the mutations, a peptide (58F63Y) with the lowest binding free energy was confirmed experimentally to have the highest affinity, and it may be used as a new probe in diagnosing and treating HER2-positive breast cancer.

Authors: Yang, X; Wang, Z; Xiang, Z; Li, D; Hu, Z

• Publication status: Published
• Peer review status: Peer reviewed
• Publisher: Public Library of Science
• Journal: PLoS Computational Biology
• Volume: 13
• Issue: 4
• Pages: e1005441-e1005441
• Publication date: 2017-04-13
• DOI: 10.1371/journal.pcbi.1005441
• EISSN: 1553-7358
• ISSN: 1553-734X
• Language: English
• Keywords: Breast cancer; Computational chemistry; Gene; Cancer; Monoclonal antibody; Chemistry; Molecular dynamics; Computational biology; Biochemistry; Pertuzumab; Biophysics; Antibody; Metastatic breast cancer; Biology; In silico; Genetics; Peptide