Human brahma-related gene 1 (Brg1) is a central ATPase protein in the human SWI/SNF chromatin remodeling complex, which is responsible for DNA replication, DNA damage response and control of the growth, division, and differentiation of cells. Structurally, it contains a bromodomain which interacts with acetylated nucleosomes, along with a small AT-hook motif that recognizes DNA and enhances the DNA-binding activity. Results of NMR and CD spectroscopy, along with isothermal calorimetry studies, suggest that the Brg1 bromodomain associates with the DNA through an interaction patch which includes residues along a helix and two adjacent loops, while the AT-hook preferentially binds in the minor groove. However, the molecular mechanisms underlying these interactions, along with the effects of simultaneous bromodomain/AT-hook binding remain unclear. Here, we have combined molecular docking, classic molecular dynamics, and multi-dimensional metadynamics simulations to investigate how the Brg1 bromodomain/AT-hook complex identifies specific binding sites along DNA and the difference with Brg1 bromodomains lacking the AT-hook. Different binding modes have been found corresponding to minor and major groove interactions, which were discriminated from one another through free energy calculations. Results reveal how the most likely configurations adopted by the Brg-AT/DNA complex during the sliding process are different than the Brg/DNA complex, indicative of distinctive binding specificity. Taken together, our results suggest that interactions between both the bromodomain and the AT-hook with DNA are involved in the dynamic process of chromatin remodelling.<br/>

Molecular dynamics and metadynamics based studies of Brg1/DNA interaction

2019 Spring National Meeting

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