Unveiling the interdomain dynamics of type II DNA topoisomerase through all-atom simulations : implications for understanding its catalytic cycle

Pavlin, Matic (author), Herlah, Barbara (author), Valjavec, Katja (author), Perdih, Andrej (author)

Type IIA DNA topoisomerases are complex molecular nanomachines that manage topological states of the DNA molecule in the cell and play a crucial role in cellular processes such as cell division and transcription. They are also established targets of cancer chemotherapy. Starting from the available crystal structure of a fully catalytic topoisomerase IIA homodimer from Saccharomyces cerevisiae, we constructed three states of this molecular motor primarily changing the configurations of the DNA segment bound in the DNA gate and performed μs-long all-atom molecular simulations. A comprehensive analysis revealed a sliding motion within the DNA gate and a teamwork between the N-gate and DNA gate that may be associated with the necessary molecular events that allow passage of the T-segment of DNA. The observed movement of the ATPase dimer relative to the DNA domain was reflected in different interaction patterns between the K-loops of the transducer domain and the B-A-B form of the bound DNA. Based on the obtained results, we mapped simulated configurations to the structures in the proposed catalytic cycle through which type IIA topoisomerases exert their function and discussed the possible transition events. The results extend our understanding of the mechanism of action of type IIA topoisomerases and provide an atomistic interpretation of some of the observed features of these molecular motors.

• Language: English
• Keywords: type IIA DNA topoisomerase, catalytic cycle, molecular simulations
• Work type: Article
• Typology: 1.01 - Original Scientific Article
• Organization: FFA - Faculty of Pharmacy
• Publication status: Published
• Publication version: Version of Record
• Year: 2023
• Number of pages: Str. 3746-3759
• Numbering: Vol. 21
• PID: 20.500.12556/RUL-164416
• UDC: 577
• ISSN on article: 2001-0370
• DOI: 10.1016/j.csbj.2023.07.019
• COBISS.SI-ID: 160446211
• Publication date in RUL: 24.10.2024

Record is a part of a journal

• Title: Computational and structural biotechnology journal
• Publisher: Elsevier, Research Network of Computational and Structural Biotechnology
• ISSN: 2001-0370
• COBISS.SI-ID: 5068826

Licences

• License: CC BY-NC-ND 4.0, Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International
• Link: http://creativecommons.org/licenses/by-nc-nd/4.0/
• Description: The most restrictive Creative Commons license. This only allows people to download and share the work for no commercial gain and for no other purposes.

Secondary language

• Language: Slovenian
• Keywords: biokemija, DNA topoizomeraza II[alfa], rakava obolenja, kemoterapija, molekularne simulacije