Molecular dynamics studies on the DNA-binding process of ERG

Abstract

The ETS family of transcription factors regulate gene targets by binding to a core GGAA DNA--sequence. The ETS factor ERG is required for homeostasis and lineage--specific functions in endothelial cells, some subset of haemopoietic cells and chondrocytes; its ectopic expression is linked to oncogenesis in multiple tissues. To date details of the DNA--binding process of ERG including DNA--sequence recognition outside the core GGAA--sequence are largely unknown. We combined available structural and experimental data to perform molecular dynamics simulations to study the DNA--binding process of ERG. In particular we were able to reproduce the ERG DNA--complex with a DNA--binding simulation starting in an unbound configuration with a final root--mean--square--deviation (RMSD) of 2.1 Å to the core ETS domain DNA--complex crystal structure. This allowed us to elucidate the relevance of amino acids involved in the formation of the ERG DNA--complex and to identify Arg385 as a novel key residue in the DNA--binding process. Moreover we were able to show that water--mediated hydrogen bonds are present between ERG and DNA in our simulations and that those interactions have the potential to achieve sequence recognition outside the GGAA core DNA--sequence. The methodology employed in this study shows the promising capabilities of modern molecular dynamics simulations in the field of protein DNA--interactions.

Molecular Dynamics Insights into Polyamine–DNA Binding Modes: Implications for Cross‐Link Selectivity

“…[24] Put, Spd, and Spm force field parameters were generated by using antechamber and RESP [30] protocols, with atom types assigned from GAFF. We note that MM-GBSA is popular,e specially to estimate DNA-drug binding, [33][34][35] although its complementary molecular mechanics Poisson Boltzmann surface area (MM-PBSA) approach is usually slightly favored for proteic systems. Then, 30 potassium counterions were added to ensure neutrality.T he system was placed in an orthorombic TIP3P [32] water box.…”

“…The entropy was computed through the quasi‐harmonic approximation. We note that MM‐GBSA is popular, especially to estimate DNA–drug binding, although its complementary molecular mechanics Poisson Boltzmann surface area (MM‐PBSA) approach is usually slightly favored for proteic systems …”

End-Point Binding Free Energy Calculation with MM/PBSA and MM/GBSA: Strategies and Applications in Drug Design

“…As powerful end-point binding free energy calculation tools, MM/PBSA and MM/GBSA have also been widely used in many other fields besides small-molecule drug design. For example, a very useful application of MM/PB­(GB)­SA is to predict the interactions between macromolecules, such as protein–protein, ,,,− protein–peptide, ,,− and protein–nucleic acid interactions. ,,− At present, calculations of the absolute binding free energies for these problems remain very challenging for alchemical methods.…”

“…With regard to protein–DNA interactions (PDIs), several recent theoretical works involving mechanistic analyses ,,− and methodology development , have been reported. For example, Peng et al developed a modified MM/PBSA method to predict the binding free energy difference arising from missense mutations to protein–DNA complexes, and a high correlation coefficient ( r P = 0.72) was reached for the test set containing 105 mutations covering 13 protein–DNA systems.…”