Vanadium complex as a potential modulator of the autophagic mechanism through proteins PI3K and ULK1: development, validation and biological implications of a specific force field for [VO(bpy)₂Cl]

Abstract

The modulation of autophagy has been presented as a very useful strategy in anticancer treatments. In this sense, the vanadium complex (VC) bis(2,2'-bipyridine)chlorooxovanadium(IV), [VO(bpy)₂Cl], is known for its ability to induce autophagy in triple-negative breast cancer cells (TNBC). An excellent resource to investigate the role of VC in the induction of autophagy is to make use of Molecular Dynamics (MD) simulations. However, until now, the scarcity of force field parameters for the VC prevented a reliable analysis. The autophagy signaling pathway starts with the PI3K protein and ends with ULK1. Therefore, in the first stage of this work, we developed a new AMBER force field for the VC (VCFF) from a quantum structure, obtained by DFT calculations. In the second stage, the VCFF was validated through structural analyses. From this, it was possible to investigate, through docking and MD (200 ns), the performance of the PI3K-VC and ULK1-VC systems (third stage). The analyses of this last stage involved RMSD, hydrogen bonds, RMSF and two pathways for the modulation of autophagy. In general, this work fills in the absence of force field parameters (FF) for VC by proposing an efficient and new FF, in addition to investigating, at the molecular level, how VC is able to induce autophagy in TNBC cells. This study encourages new parameterizations of metallic complexes and contributes to the understanding of the duality of autophagic processes.

Communicated by Ramaswamy H. Sarma

Keywords:

• Autophagy
• modulation
• vanadium complex
• AMBER force field
• molecular dynamics

Acknowledgements

The authors thank the Brazilian agencies CNPq, FAPEMIG and CAPES for the financial support. In addition, we would like to thank M.Sc. Ander Francisco Pereira for all the support in the methodology and discussions of this work, which certainly contributed to improve this study.

Authors’ contributions

TMRS developed the project; TMRS, TCR, CAT and EFFC analyzed the data; TMRS, wrote the paper; TMRS designed the figures; TCR, CAT and EFFC proofread the manuscript.

Consent for publication

All authors fully agree with the content of this work and are aware of the publication.

Data availability statement

The authors provide a Supporting Information (SI) file to complement the results and discussions presented in this manuscript.

Disclosure statement

The authors declare no conflict of interest.

Additional information

Funding

This work was carried out with the financial support of the Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq, 307837/2014-9) and the Fundação de Amparo à Pesquisa do Estado de Minas Gerais (FAPEMIG, PPM-00831-15).