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

Abstract

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.

Computer Simulation of the Interaction between SARS-CoV-2 Spike Protein and the Surface of Coinage Metals

“…Also, 2 ns of NVT productions were done for wetting calculations. The Berendsen thermostat has been widely employed in previous simulation works of proteins, showing good agreement with experiments [92][93][94][95]. During the .…”

“…Also, 2 ns of NVT productions were done for wetting calculations. The Berendsen thermostat has been widely employed in previous simulation works of proteins, showing good agreement with experiments. − During the simulations, a 1.0 nm cutoff for LJ and Coulomb interactions was applied and the particle mesh Ewald method , was used for long-range electrostatics.…”

Molecular Dynamics Simulations of Adsorption of SARS-CoV-2 Spike Protein on Polystyrene Surface

“…Then, we performed a 200 ns NVT production run (2 ns for wetting calculations) at 300 K using a Berendsen thermostat with a damping constant of 0.1 ps. This thermostat has been widely employed in previous simulation works of proteins, showing good agreement with experiments. − During the simulations, a 1.0 nm cutoff for Lennard-Jones (LJ) and Coulomb interactions was applied and the particle mesh-Ewald method , was used for long-range electrostatics. The LINCS method was also used as a constraint algorithm.…”

Probing the Energy Landscape of Spectrin R15 and R16 and the Effects of Non-native Interactions

“…M is the number of hydrophobic amino acids; K HP = 0.1 is the overall strength of the hydrophobic forces, and r ij HP represents the distance between two non-native hydrophobic amino acids (Ala, Val, Leu, Ile, Met, Trp, and Phe), with σ = 5 Å, which is the minimum interaction distance. The last term, the Debey-Hückel model − represents the electrostatic interactions by adding charged points at beads in all acidic/basic residues (i.e., Arg, His, Lys, Glu, and Asp). The charged residues, i and j , are represented by q i and q j ; K Elec = 332 kcalÅ/(mol e 2 ).…”