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Molecular simulations of paclitaxel binding to mutant β-tubulin: insights into chemotherapy resistance
Paola Vottero1, Martina Centroni2, Ebenezea Gitari1
1Department of Biomedical Engineering, University of Alberta, Edmonton, T6G 1H9, Canada.
Abstract:
Paclitaxel, a cornerstone in cancer chemotherapy, stabilizes microtubules by binding to the β-tubulin taxane site. However, resistance mechanisms, often driven by β-tubulin mutations, undermine its efficacy. While such mutations are known to alter drug sensitivity, their molecular impact on paclitaxel binding remains incompletely understood. Here, we employ molecular docking, molecular dynamics (MD) simulations, and Molecular Mechanics with Generalized Born Surface Area (MM/GBSA) calculations to quantify how clinically relevant β-tubulin mutations affect paclitaxel binding affinity. Root mean square fluctuation (RMSF) analysis was used to assess local structural dynamics near the binding site. Our results show that despite minor variations in docking scores, MM/GBSA analyses revealed significant mutation-induced shifts in binding free energy, particularly for residues near the M loop, H5-H6 helices, and S9-S10 region. Complementary RMSF analysis indicated altered flexibility in several of these regions, suggesting potential disruptions to local stabilization mechanisms. Differences between single- and two-dimer simulations highlight the importance of modeling lateral protofilament contacts when evaluating microtubule-targeting agents. These findings underscore the relevance of structure-based modeling for understanding drug resistance mechanisms and informing the development of mutation-aware taxane therapies.
Insights
Clinically relevant mutations in beta-tubulin (β-tubulin) can reduce paclitaxel chemotherapy effectiveness. This study used computational methods to reveal how these mutations alter paclitaxel binding at a molecular level.
Area of Science:
- Biochemistry
- Computational Biology
- Pharmacology
Background:
- Paclitaxel is a vital chemotherapy drug that stabilizes microtubules.
- Drug resistance, often due to mutations in β-tubulin, limits paclitaxel's effectiveness.
- The precise molecular mechanisms by which β-tubulin mutations affect paclitaxel binding are not fully understood.
Purpose of the Study:
- To investigate the molecular impact of clinically relevant β-tubulin mutations on paclitaxel binding affinity.
- To quantify changes in binding free energy and local structural dynamics caused by these mutations.
- To inform the development of next-generation taxane therapies that overcome resistance.
Main Methods:
- Molecular docking simulations were performed to predict paclitaxel binding poses.
- Molecular dynamics (MD) simulations were used to analyze the dynamic behavior of mutated β-tubulin.
- Molecular Mechanics with Generalized Born Surface Area (MM/GBSA) calculations quantified binding free energies.
- Root mean square fluctuation (RMSF) analysis assessed local structural flexibility.
Main Results:
- MM/GBSA calculations revealed significant changes in paclitaxel binding free energy due to mutations, particularly affecting key regions like the M loop and H5-H6 helices.
- RMSF analysis indicated altered flexibility in mutation-affected regions, suggesting disrupted stabilization mechanisms.
- Simulations incorporating lateral protofilament contacts provided deeper insights than single-dimer models.
Conclusions:
- Clinically relevant β-tubulin mutations significantly alter paclitaxel binding affinity and dynamics.
- Structure-based computational modeling is crucial for understanding drug resistance mechanisms.
- These findings can guide the design of paclitaxel derivatives effective against resistant cancer strains.
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