Allosteric Analysis of Glucocorticoid Receptor-DNA Interface Induced by Cyclic Py-Im Polyamide: A Molecular Dynamics Simulation Study

作者：Wang, Yaru; Ma, Na; Wang, Yan; Chen, Guangju

来源：PLos One, 2012, 7(4): e35159.

DOI：10.1371/journal.pone.0035159

• AMBER FORCE-FIELD
• BINDING DOMAIN
• MINOR-GROOVE
• UNSTRUCTURED REGION
• CONTINUUM SOLVENT
• STRUCTURAL BASIS
• NUCLEIC-ACIDS
• RECOGNITION
• PROTEIN
• INHIBITION

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

• 出版日期2012-4-19
• 单位北京师范大学