Engineered BCL6 BTB Domain of the Bcl-2 Protein Family shows Dynamic Structural Behavior: Insights from Molecular Dynamics Simulations

Abstract

AbstractApoptosis is crucially regulated by the Bcl-6 protein, and mutations in this protein can have a significant impact on many malignancies. In this study, we used molecular dynamics simulations to examine the effects of specific mutations (Q8C, R67C, and N84C) in the crystal structure of the BCL6 BTB domain in a compound with pyrazole-pyrimidine ligand. We concentrated on comprehending the dynamics of these alterations and their possible effects on the emergence of cancer. To explore the structural and dynamic changes induced by these mutations, we performed in silico simulations using the GROMACS software suite (version 5.2, 2020.1) on Google Colab’s Tesla T4 GPU. The crystal structure of the BCL6 BTB domain in complex with the pyrazole-pyrimidine ligand (PDB ID: 5N20) served as the wild-type reference structure. Mutations were imposed using the Rotamer functions of Chimera. The simulations were carried out for a total duration of 20 ns using a time step of 2 femtoseconds (0.002 ps). The Trajectory profiles of the BCL6 BTB domain protein and its three mutations, Q8C, R67C and N84C, were shown to differ from each other. Based on the analysis of RMSD, RMSF, and Rg, it was determined that the mutant 2 (R67C) protein exhibited increased instability and greater flexibility. In contrast, mutant 3 (N84C) demonstrates a heightened level of compactness and greater stability compared to the remaining protein mutant. PCA also provides information regarding the structural dynamics of these mutants. In addition, the SASA and SASA autocorrelation provides a distinct view of the solvent accessibility of these proteins.