Post-translational modifications of histone tails regulate chromatin structure and gene expression. However, little is known on the relationship between molecular recognition and epigenetic regulation. Lysine-Specific Demethylase-1 (LSD1), a histone-modifying enzyme, associated with its co-repressor protein CoREST catalyzes the oxidative demethylation of Lys4 of Histone H3 protein, an important marker for the epigenetic modulation of chromatin. However, our current understanding on the relationship between binding thermodynamics and epigenetic regulation is poor. Here, we present new studies on peptide molecular recognition using enhanced-sampling and molecular dynamics simulations to elucidate the recognition mechanism displayed by the H3 pocket and the thermodynamic forces driving binding. Due to the high sequence conservation of H3 peptide with SNAIL/SCRATCH superfamily of transcription factors, unravels the potential of LSD1-CoREST as a multiple docking site for other proteins. Our study provides new fundamental understanding of LSD1-CoREST molecular recognition, with relevance to expand the chemical diversity of LSD1 epigenetic inhibitors.  REFERENCES: Baron R, Binda C, Tortorici M, McCammon JA, Mattevi A. Molecular Mimicry and Ligand Recognition in Binding and Catalysis by the Histone Demethylase LSD1-CoREST Complex, Structure, 19, 212-220, 2011. PMID: 21300290.Baron R, Vellore NA. Reversible Opening/Closing Dynamics of LSD/CoREST: Computational Discovery of a Nanoscale Clamp for Chromatin and Protein Binding, Biochemistry, under review.Vellore NA, Baron R. Computational Screening of the Lysine Specific Demethylase 1 (LSD1/KDM1A) Target for Epigenetic Anticancer Drugs Using Alternative Receptor Structures and Docking Algorithms. In preparation.

Molecular recognition and epigenetic modulation: The LSD1-CoREST nanoscale clamp prototype system

244th National Meeting (2012)

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