Molecular Dynamics Analysis of  ET Domain-Peptide Interactions in BET Family Proteins

Elizabeth Sebastian, Arup Mondal, Alberto Perez

University of Florida

Bromodomain and extraterminal (BET) domain containing proteins such as BRD3 and BRD4 are regulatory proteins that increase transcription of euchromatin through binding to lysine-acetylated histones and recruiting transcription factors to the transcription start site¹. The extra-terminal (ET) domain acts as a protein interaction hub to recruit these regulatory proteins². Some viral peptides also bind to the ET domain to associate close to the transcription start site. What is unique about the ET receptor is that it exhibits a large degree of plasticity, binding different peptides through different binding modes³. BET proteins are associated with multiple types of cancers and are possible targets for gene therapy – but the mechanism by which ET helps regulate the process is unknown⁴. The peptide binding region in the ET domain of BET provides a possible target for a cancer therapeutic, but differences in binding affinity between BRD3 and BRD4 have yet to be understood. Differences in structure configuration in the ET domain after a binding event will be elucidated using a combination of advanced computational techniques including adaptive sampling molecular dynamics (MD) and Markov state modeling. By determining the dynamical and structural changes during binding, it is possible to identify a drug target that differentiates between BRD3 and BRD4 allowing for future drug development.

Works Cited:

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