LSD1/CoREST - H3-Histone Molecular Recognition: Inter-Domain Motions in an Allosteric Nanoscale Clamp Revealed by Computer Simulations

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The protein complex of Lysine Specific Demethylase-1 (LSD1) with its co-repressor (LSD1/CoREST) catalyzes the demethylation of the H3-histone N-terminal tail and is a target of outstanding relevance for drugs against cancer and neurodegenerative disorders. However, little is known to date on the relationship between LSD1/CoREST molecular recognition and the molecular mechanisms of epigenetic modulation. Using molecular dynamics simulation, we have previously shown that LSD1/CoREST is a highly dynamic nanoscale clamp; we proposed that binding of the H3-histone N-terminal tail reduces the clamp rotation around the Tower domain by means of an allosteric mechanism. Here, we present new studies of LSD1/CoREST clamp dynamics and substrate recognition using adaptive biasing force simulations to detail the biophysical nature of the previously discovered motion. The allosteric mechanism is found to be qualitatively independent of the force field and of the sampling approach employed. Free energy profiles are obtained using enhanced sampling approaches. Overall, our study reveals an unprecedented view on LSD1/CoREST molecular recognition and dynamics and paves a route for a more general understanding of epigenetic regulation at the molecular level, thus aiding future drug discovery campaigns.1. Shi Y, Nat. Rev. Genet. 2007, 8, 829.2. Forneris F et al. LSD1: oxidative chemistry for multifaceted functions in chromatin regulation. TiBS, 2008, 33,181.3. Baron R; Vellore NA. LSD1/CoREST is an allosteric-nanoscale clamp regulated by H3-histone-tail molecular recognition. PNAS 2012, 109, 12509.4. Baron R; Vellore NA, LSD1/CoREST reversible opening-closing dynamics: discovery of a nanoscale clamp for chromatin and protein binding. Biochemistry 2012, 51, 3151.5. Robertson JC et al. Expanding the Druggable Space of the LSD1/CoREST Epigenetic Target: New Potential Binding Regions for Drug-Like Molecules, Peptides, Protein Partners, and Chromatin, PLoS Comput. Biol. 2013, 9(7): e1003158.