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Comparative binding analysis of monoclonal antibodies against native and mutant type in ErbB2 receptor: a theoretical
R Rajasekaran1, Sethumadhavan Rao
1School of Biotechnology, Chemical and Biomedical Engineering, Bioinformatics Division, Vellore Institute of Technology University, Tamil Nadu, India.
Abstract:
Trastuzumab and pertuzumab are monoclonal antibodies, used for inhibiting the ErbB2 receptor which is over expressed in breast and ovarian cancer. In this study, we identified that the most detrimental single point mutation is from tryptophan to cysteine at the residue position of 452 on ErbB2 receptor by using I-Mutant 2.0, SIFT and PolyPhen programs. The modeled mutant showed less stability than native ErbB2 protein based on both total energy of the mutant and stabilizing residues in the mutant protein. This is due to deviation between the mutant and native ErbB2 having the RMSD of about 2.83A. Further, we found, pertuzumab showed a marginal higher binding affinity with ErbB2 receptor of native and mutant type with a binding free energy of -16.01 kcal/mole each as compared to trastuzumab, showing a binding free energy of -15.26 kcal/mole in ErbB2 of native type. On the contrary, trastuzumab showed a remarkably high binding affinity with ErbB2 receptor of mutant type having the binding free energy -24.40 kcal/mol. Moreover, the reason for high binding efficiency of trastuzumab with mutant ErbB2 is due to additional hydrogen bonding of amino acid Asn30 of trastuzumab with Asp596 and Glu598 of ErbB2 receptor of mutant type. Based on this work, we propose that pertuzumab could be the potential monoclonal antibody against ErbB2 for native type and trastuzumab could be the potential monoclonal antibody against ErbB2 of mutant type. Therefore combined administration of trastuzumab and pertuzumab could be a novel strategy for breast cancer treatment.
Insights
A specific ErbB2 mutation (Trp452Cys) impacts protein stability. Trastuzumab shows higher affinity for mutant ErbB2, suggesting combined antibody therapy for breast cancer.
Area of Science:
- Molecular Biology
- Oncology
- Biochemistry
Background:
- ErbB2 receptor overexpression is common in breast and ovarian cancers.
- Trastuzumab and pertuzumab are monoclonal antibodies targeting the ErbB2 receptor.
Purpose of the Study:
- To identify detrimental mutations in the ErbB2 receptor.
- To compare the binding affinities of trastuzumab and pertuzumab to native and mutant ErbB2.
- To propose novel therapeutic strategies for ErbB2-positive cancers.
Main Methods:
- In silico analysis using I-Mutant 2.0, SIFT, and PolyPhen to predict mutation effects.
- Molecular modeling to assess protein stability and deviations (RMSD).
- Binding free energy calculations to quantify antibody-receptor interactions.
Main Results:
- The tryptophan to cysteine mutation at residue 452 (Trp452Cys) was identified as the most detrimental, reducing ErbB2 stability.
- Pertuzumab exhibited slightly higher binding affinity to both native and mutant ErbB2 compared to trastuzumab.
- Trastuzumab demonstrated significantly enhanced binding affinity to the mutant ErbB2, attributed to additional hydrogen bonds.
Conclusions:
- Pertuzumab is a potential antibody for native ErbB2, while trastuzumab is effective against mutant ErbB2.
- Combined administration of trastuzumab and pertuzumab represents a novel therapeutic strategy for breast cancer.
- Understanding mutation-specific antibody efficacy can guide personalized cancer treatment.
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