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Published on: May 15, 2019
Inhibition of cMYC-MAX transcription factors hetero-dimerization with structurally engineered omoMYC to downregulate
Wenfeng Li1, Farah Bano2, Abbas Khan3
1Department of Urology, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
Abstract:
In the current study, we employed, structural informatics, and molecular simulation-based methods to engineer OmoMyc, a c-Myc dominant negative protein, to design novel mutants that could abrogate the c-MYC-MAX complex in Renal Carcinoma (RC). Among the total 472 mutations, only six mutations A61Q, Q64E, Q64K, N77R, Q64E-N77R, and Q64K-N77R were reported to increase the binding affinity and subjected to subsequent analysis such as protein-protein docking. The docking results revealed that the predicted mutants improve the functionality of the OmoMyc by not only increasing the binding affinity but also vdW and electrostatic energy in each complex that consequently increase the binding of the engineered OmoMyc by establishing extra hydrogen bonds, salt-bridges, and non-bonded contacts. Molecular simulation revealed a more stable behavior by the mutant complexes in contrast to the native OmoMyc however structural perturbations were reported in the regions, DBD (DNA-binding domain), loop region, and minor deviations at CTD (C terminal domain). Moreover, the hydrogen bonding and binding free energy results further validated the promising activity of our predicted mutants of OmoMyc. The results for TBE (total binding energy) revealed that the for each complex the TBE was calculated to be -87.88 ± 0.16 kcal/mol (WT OmoMyc-MAX), -91.89 ± 0.21 kcal/mol (A61Q OmoMyc-MAX), -91.55 ± 0.20 kcal/mol (Q64E OmoMyc-MAX), -95.17 ± 0.24 kcal/mol (Q64K OmoMyc-MAX), -96.49 ± 0.22 kcal/mol (N77R OmoMyc-MAX), -97.76 ± 0.22 kcal/mol (Q64E-N77R OmoMyc-MAX), and -95.31 ± 0.20 kcal/mol (Q64K-N77R OmoMyc-MAX) respectively. The results for TBE revealed promising results that allow the mutants to competitively inhibit the c-Myc-MAX complex more swiftly. Additionally, the internal motion and energy landscape were altered. These findings provide important insights into the potential of the mutants of OmoMyc as a therapeutic candidate for cancer treatment, particularly renal carcinoma, and could pave the way for the development of more effective clinical versions of OmoMyc.
Insights
Engineered OmoMyc mutants show enhanced binding affinity to abrogate the c-Myc-MAX complex in renal carcinoma. These novel protein variants demonstrate increased stability and therapeutic potential for cancer treatment.
Area of Science:
- Biochemistry and Structural Biology
- Computational Chemistry
- Oncology
Background:
- The c-Myc oncoprotein plays a critical role in cell proliferation and is frequently dysregulated in various cancers, including renal carcinoma (RC).
- The c-Myc/MAX dimerization is essential for c-Myc's transcriptional activity, making it a key therapeutic target.
- Developing dominant-negative proteins like OmoMyc is a strategy to inhibit oncogenic protein interactions.
Purpose of the Study:
- To engineer novel OmoMyc mutants with abrogated c-Myc/MAX complex binding using structural informatics and molecular simulations.
- To identify specific mutations that enhance binding affinity and inhibitory function against the c-Myc/MAX complex in renal carcinoma.
Main Methods:
- Employed structural informatics and molecular simulation-based methods for protein engineering.
- Designed and analyzed 472 mutations in OmoMyc, focusing on those that enhance binding affinity.
- Utilized protein-protein docking and molecular dynamics simulations to assess mutant stability and interactions.
Main Results:
- Six specific mutations (A61Q, Q64E, Q64K, N77R, Q64E-N77R, Q64K-N77R) significantly increased OmoMyc's binding affinity to the c-Myc/MAX complex.
- Mutants demonstrated improved binding through increased van der Waals and electrostatic energies, forming additional hydrogen bonds and salt bridges.
- Molecular simulations indicated enhanced stability of mutant complexes compared to wild-type OmoMyc, despite minor structural perturbations in specific domains.
Conclusions:
- The engineered OmoMyc mutants exhibit promising therapeutic potential for renal carcinoma by effectively inhibiting the c-Myc/MAX complex.
- These findings provide a foundation for developing more effective clinical OmoMyc-based cancer therapies.
- The study highlights the utility of computational approaches in designing targeted protein therapeutics.
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