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Unveiling dissociation mechanisms and binding patterns in the UHRF1-DPPA3 complex via multi-replica molecular dynamics simulations

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Abstract

Context

Ubiquitin-like with PHD and RING finger domain containing protein 1 (UHRF1) is responsible for preserving the stability of genomic methylation through the recruitment of DNA methyltransferase 1 (DNMT1). However, the interaction between Developmental pluripotency associated 3 (DPPA3) and the pre-PHD-PHD (PPHD) domain of UHRF1 hinders the nuclear localization of UHRF1. This disruption has implications for potential cancer treatment strategies. Drugs that mimic the binding pattern between DPPA3 and PPHD could offer a promising approach to cancer treatment. Our study reveals that DPPA3 undergoes dissociation from the C-terminal through three different modes of helix unfolding. Furthermore, we have identified key residue pairs involved in this dissociation process and potential drug-targeting residues. These findings offer valuable insights into the dissociation mechanism of DPPA3 from PPHD and have the potential to inform the design of novel drugs targeting UHRF1 for cancer therapy.

Methods

To comprehend the dissociation process and binding patterns of PPHD-DPPA3, we employed enhanced sampling techniques, including steered molecular dynamics (SMD) and conventional molecular dynamics (cMD). Additionally, we utilized self-organizing maps (SOM) and time-resolved force distribution analysis (TRFDA) methodologies. The Gromacs software was used for performing molecular dynamics simulations, and the AMBER FF14SB force field was applied to the protein.

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Data availability

Data available on request from the authors.

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Acknowledgements

We express our heartfelt appreciation to the Yang Lab at Nankai University, College of Pharmacy for their invaluable inspiration. Their expertise and research contributions have significantly influenced the development of this research.

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Authors and Affiliations

  1. Institute for Fetology, The First Affiliated Hospital of Soochow University, Suzhou, 215006, China

    Lei He

  2. State Key Laboratory of Medicinal Chemical Biology, College of Pharmacy, Nankai University, Tianjin, 300353, China

    Longxiao Yuan

  3. School of Computer Sciences and Technology, Tiangong University, Tianjin, 300387, China

    Xiaodan Liang

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  1. Longxiao Yuan
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Contributions

Lei He: conceptualization, supervision; Longxiao Yuan: methodology, visualization, data curation, writing — original draft preparation. Xiaodan Liang: provision of computational resources. Lei He and Longxiao Yuan: writing — review and editing.

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Correspondence to Xiaodan Liang or Lei He.

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Yuan, L., Liang, X. & He, L. Unveiling dissociation mechanisms and binding patterns in the UHRF1-DPPA3 complex via multi-replica molecular dynamics simulations. J Mol Model 30, 173 (2024). https://doi.org/10.1007/s00894-024-05946-9

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