Detailed Per-residue Energetic Analysis Explains the Driving Force for Microtubule Disassembly.
Microtubules are long filamentous hollow cylinders whose surfaces form lattice structures of αβ-tubulin heterodimers. They perform multiple physiological roles in eukaryotic cells and are targets for therapeutic interventions. In our study, we carried out all-atom molecular dynamics simulations for...
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Public Library of Science (PLoS)
2015-06-01
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| Series: | PLoS Computational Biology |
| Online Access: | https://doi.org/10.1371/journal.pcbi.1004313 |
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| author | Ahmed T Ayoub Mariusz Klobukowski Jack A Tuszynski |
| author_facet | Ahmed T Ayoub Mariusz Klobukowski Jack A Tuszynski |
| author_sort | Ahmed T Ayoub |
| collection | DOAJ |
| description | Microtubules are long filamentous hollow cylinders whose surfaces form lattice structures of αβ-tubulin heterodimers. They perform multiple physiological roles in eukaryotic cells and are targets for therapeutic interventions. In our study, we carried out all-atom molecular dynamics simulations for arbitrarily long microtubules that have either GDP or GTP molecules in the E-site of β-tubulin. A detailed energy balance of the MM/GBSA inter-dimer interaction energy per residue contributing to the overall lateral and longitudinal structural stability was performed. The obtained results identified the key residues and tubulin domains according to their energetic contributions. They also identified the molecular forces that drive microtubule disassembly. At the tip of the plus end of the microtubule, the uneven distribution of longitudinal interaction energies within a protofilament generates a torque that bends tubulin outwardly with respect to the cylinder's axis causing disassembly. In the presence of GTP, this torque is opposed by lateral interactions that prevent outward curling, thus stabilizing the whole microtubule. Once GTP hydrolysis reaches the tip of the microtubule (lateral cap), lateral interactions become much weaker, allowing tubulin dimers to bend outwards, causing disassembly. The role of magnesium in the process of outward curling has also been demonstrated. This study also showed that the microtubule seam is the most energetically labile inter-dimer interface and could serve as a trigger point for disassembly. Based on a detailed balance of the energetic contributions per amino acid residue in the microtubule, numerous other analyses could be performed to give additional insights into the properties of microtubule dynamic instability. |
| format | Article |
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| issn | 1553-734X 1553-7358 |
| language | English |
| publishDate | 2015-06-01 |
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| spelling | doaj-art-d7478414d1ba4da28ff54cb728ba4cc82025-08-20T02:22:24ZengPublic Library of Science (PLoS)PLoS Computational Biology1553-734X1553-73582015-06-01116e100431310.1371/journal.pcbi.1004313Detailed Per-residue Energetic Analysis Explains the Driving Force for Microtubule Disassembly.Ahmed T AyoubMariusz KlobukowskiJack A TuszynskiMicrotubules are long filamentous hollow cylinders whose surfaces form lattice structures of αβ-tubulin heterodimers. They perform multiple physiological roles in eukaryotic cells and are targets for therapeutic interventions. In our study, we carried out all-atom molecular dynamics simulations for arbitrarily long microtubules that have either GDP or GTP molecules in the E-site of β-tubulin. A detailed energy balance of the MM/GBSA inter-dimer interaction energy per residue contributing to the overall lateral and longitudinal structural stability was performed. The obtained results identified the key residues and tubulin domains according to their energetic contributions. They also identified the molecular forces that drive microtubule disassembly. At the tip of the plus end of the microtubule, the uneven distribution of longitudinal interaction energies within a protofilament generates a torque that bends tubulin outwardly with respect to the cylinder's axis causing disassembly. In the presence of GTP, this torque is opposed by lateral interactions that prevent outward curling, thus stabilizing the whole microtubule. Once GTP hydrolysis reaches the tip of the microtubule (lateral cap), lateral interactions become much weaker, allowing tubulin dimers to bend outwards, causing disassembly. The role of magnesium in the process of outward curling has also been demonstrated. This study also showed that the microtubule seam is the most energetically labile inter-dimer interface and could serve as a trigger point for disassembly. Based on a detailed balance of the energetic contributions per amino acid residue in the microtubule, numerous other analyses could be performed to give additional insights into the properties of microtubule dynamic instability.https://doi.org/10.1371/journal.pcbi.1004313 |
| spellingShingle | Ahmed T Ayoub Mariusz Klobukowski Jack A Tuszynski Detailed Per-residue Energetic Analysis Explains the Driving Force for Microtubule Disassembly. PLoS Computational Biology |
| title | Detailed Per-residue Energetic Analysis Explains the Driving Force for Microtubule Disassembly. |
| title_full | Detailed Per-residue Energetic Analysis Explains the Driving Force for Microtubule Disassembly. |
| title_fullStr | Detailed Per-residue Energetic Analysis Explains the Driving Force for Microtubule Disassembly. |
| title_full_unstemmed | Detailed Per-residue Energetic Analysis Explains the Driving Force for Microtubule Disassembly. |
| title_short | Detailed Per-residue Energetic Analysis Explains the Driving Force for Microtubule Disassembly. |
| title_sort | detailed per residue energetic analysis explains the driving force for microtubule disassembly |
| url | https://doi.org/10.1371/journal.pcbi.1004313 |
| work_keys_str_mv | AT ahmedtayoub detailedperresidueenergeticanalysisexplainsthedrivingforceformicrotubuledisassembly AT mariuszklobukowski detailedperresidueenergeticanalysisexplainsthedrivingforceformicrotubuledisassembly AT jackatuszynski detailedperresidueenergeticanalysisexplainsthedrivingforceformicrotubuledisassembly |