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Int. J. Mol. Sci. 2013, 14(8), 16836-16850; doi:10.3390/ijms140816836

Trastuzumab-Peptide Interactions: Mechanism and Application in Structure-Based Ligand Design

* ,
*  and
Soft Matter Research Center, Department of Chemistry, Zhejiang University, Hangzhou 310027, China
* Authors to whom correspondence should be addressed.
Received: 15 July 2013 / Revised: 31 July 2013 / Accepted: 6 August 2013 / Published: 15 August 2013
(This article belongs to the collection Proteins and Protein-Ligand Interactions)
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Understanding of protein-ligand interactions and its influences on protein stability is necessary in the research on all biological processes and correlative applications, for instance, the appropriate affinity ligand design for the purification of bio-drugs. In this study, computational methods were applied to identify binding site interaction details between trastuzumab and its natural receptor. Trastuzumab is an approved antibody used in the treatment of human breast cancer for patients whose tumors overexpress the HER2 (human epidermal growth factor receptor 2) protein. However, rational design of affinity ligands to keep the stability of protein during the binding process is still a challenge. Herein, molecular simulations and quantum mechanics were used on protein-ligand interaction analysis and protein ligand design. We analyzed the structure of the HER2-trastuzumab complex by molecular dynamics (MD) simulations. The interaction energies of the mutated peptides indicate that trastuzumab binds to ligand through electrostatic and hydrophobic interactions. Quantitative investigation of interactions shows that electrostatic interactions play the most important role in the binding of the peptide ligand. Prime/MM-GBSA calculations were carried out to predict the binding affinity of the designed peptide ligands. A high binding affinity and specificity peptide ligand is designed rationally with equivalent interaction energy to the wild-type octadecapeptide. The results offer new insights into affinity ligand design.
Keywords: protein-ligand interaction; binding pocket; binding mechanism; peptide design; molecular dynamics; MM-GBSA protein-ligand interaction; binding pocket; binding mechanism; peptide design; molecular dynamics; MM-GBSA
This is an open access article distributed under the Creative Commons Attribution License (CC BY) which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

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Sun, T.-Y.; Wang, Q.; Zhang, J.; Wu, T.; Zhang, F. Trastuzumab-Peptide Interactions: Mechanism and Application in Structure-Based Ligand Design. Int. J. Mol. Sci. 2013, 14, 16836-16850.

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