Allosteric analysis of glucocorticoid receptor-DNA interface induced by cyclic Py-Im polyamide: a molecular dynamics simulation study.

摘要: Background It has been extensively developed in recent years that cell-permeable small molecules, such as polyamide, can be programmed to disrupt transcription factor-DNA interfaces and silence aberrant gene expression. For example, cyclic pyrrole-imidazole polyamide competes with glucocorticoid receptor (GR) for binding response elements could expected affect the DNA dependent by interfering protein-DNA interface. However, how molecules regulatory pathways through structure distortion is not fully understood so far. Methodology/Principal Findings In present work, we have constructed some models, especially ternary model of polyamides+DNA+GR DNA-binding domain (GRDBD) dimer, carried out molecular dynamics simulations free energy calculations them address GRDBD interface when protein bind at same sites on opposite grooves DNA. Conclusions/Significance We found minor groove induce a large structural perturbation DNA, i.e. >4 A widening compression major more than 4 compared molecule dimer+DNA complex. Further investigations system polyamides+DNA+GRDBD dimer binary allosteric DNA+GRDBD revealed surface causes move away from initial average distance ∼4 final ∼10 during 40 ns simulation course. Therefore, this study straightforward explores targeting specific disrupts groove, consequently modulates