Coarse-Grained Simulations of Protein Folding: Bridging Theory and Experiments

Contessoto, Vinícius G.; Oliveira, Vinícius Martins de; Leite, Vitor Barbanti Pereira

doi:10.1007/978-1-0716-1716-8_16

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“…We performed constant-pH molecular dynamics simulations using the db-SBM to obtain trajectories with several transitions between the ER active and inactive state; these states are presented in Figure A. This model is based on the concept of the energy landscape theory and is often used to explore protein folding and biomolecular rearrangements. − ,, Despite the limitations of using a coarse-grained implicit solvent model, the computational results applying SBM have successfully provided an understanding of the physical principles that govern molecular dynamics in several systems. ,,,,, Such previous success motivated us to use it to investigate the process of activation of the ER.…”

Section: Resultsmentioning

confidence: 99%

pH and the Breast Cancer Recurrent Mutation D538G Affect the Process of Activation of Estrogen Receptor α

et al. 2022

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Estrogen receptor α (ERα) is a regulatory protein that can access a set of distinct structural configurations. ERα undergoes extensive remodeling as it interacts with different agonists and antagonists, as well as transcription activation and repression factors. Moreover, breast cancer tumors resistant to hormone therapy have been associated with the imbalance between the active and inactive ERα states. Cancer-activating mutations in ERα play a crucial role in this imbalance and can promote the progression of cancer. However, the rate of this progression can also be increased by dysregulated pH in the tumor microenvironment. Many molecular aspects of the process of activation of ERα that can be affected by these pH changes and mutations are still unclear. Thus, we applied computational and experimental techniques to explore the activation process dynamics of ER for environments with different pHs and in the presence of one of the most recurrent cancer-activating mutations, D538G. Our results indicated that the effect of the pH increase associated with the D538G mutation promoted a robust stabilization of the active state of ER. We were also able to determine the main protein regions that have the most potential to influence the activation process under different pH conditions, which may provide targets of future therapeutics for the treatment of hormone-resistant breast cancer tumors. Finally, the approach used here can be applied for proteins associated with the proliferation of other cancer types, which can also have their function affected by small pH changes.

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