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Open Access Highly Accessed Research article

Molecular dynamics simulations indicate an induced-fit mechanism for LSD1/CoREST-H3-histone molecular recognition

Nadeem A Vellore and Riccardo Baron*

Author Affiliations

Department of Medicinal Chemistry, College of Pharmacy, and The Henry Eyring Center for Theoretical Chemistry, The University of Utah, Salt Lake City, UT 84112-5820, USA

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BMC Biophysics 2013, 6:15  doi:10.1186/2046-1682-6-15

Published: 25 November 2013



Lysine Specific Demethylase (LSD1 or KDM1A) in complex with its co-repressor protein CoREST catalyzes the demethylation of the H3 histone N-terminal tail and is currently one of the most promising epigenetic targets for drug discovery against cancer and neurodegenerative diseases. Models of non-covalent binding, such as lock and key, induced-fit, and conformational selection could help explaining the molecular mechanism of LSD1/CoREST-H3-histone association, thus guiding drug discovery and design efforts. Here, we quantify the extent to which LSD1/CoREST substrate binding is consistent with these hypothetical models using LSD1/CoREST conformational ensembles obtained through extensive explicit solvent molecular dynamics (MD) simulations.


We find that an induced-fit model is the most representative of LSD1/CoREST-H3-histone non-covalent binding and accounts for the local conformational changes occurring in the H3-histone binding site. We also show that conformational selection – despite in principle not ruled out by this finding – is minimal, and only relevant when global properties are considered, e.g. the nanoscale motion of the LSD1/CoREST clamp.


The induced-fit mechanism revealed by our MD simulation study will aid the inclusion of protein dynamics for the discovery and design of LSD1 inhibitors targeting the H3-histone binding region. On a general basis, our study indicates the importance of using multiple metrics or selection schemes when testing alternative hypothetical mechanistic models of non-covalent binding.

Epigenetics; Chromatin remodeling; Computer simulation; Conformational clustering; Conformational ensemble; Histone; Protein binding; Statistical test; Kolmogorov-Smirnov statistics