In this communication we introduce an efficient implementation of adaptive biasing that greatly improves the speed of free energy computation in molecular dynamics simulations. We investigated the use of accelerated simulations to inform on compound design using a recently reported and clinically relevant inhibitor of the chromatin regulator BRD4 (bromodomain-containing protein 4). Benchmarking on our local compute cluster, our implementation achieves up to 2.5 times more force calls per day than plumed2. Results of five 1 μs-long simulations are presented, which reveal a conformational switch in the BRD4 inhibitor between a binding competent and incompetent state. Stabilization of the switch led to a −3 kcal/mol improvement of absolute binding free energy. These studies suggest an unexplored ligand design principle and offer new actionable hypotheses for medicinal chemistry efforts against this druggable epigenetic target class.
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21 October 2016
Research Article|
October 19 2016
A fast, open source implementation of adaptive biasing potentials uncovers a ligand design strategy for the chromatin regulator BRD4
Bradley M. Dickson;
Bradley M. Dickson
a)
1Center for Epigenetics,
Van Andel Research Institute
, 333 Bostwick Avenue, NE, Grand Rapids, Michigan 49503, USA
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Parker W. de Waal
;
Parker W. de Waal
2Laboratory of Structural Sciences,
Van Andel Research Institute
, 333 Bostwick Avenue, NE, Grand Rapids, Michigan 49503, USA
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Zachary H. Ramjan;
Zachary H. Ramjan
1Center for Epigenetics,
Van Andel Research Institute
, 333 Bostwick Avenue, NE, Grand Rapids, Michigan 49503, USA
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H. Eric Xu;
H. Eric Xu
2Laboratory of Structural Sciences,
Van Andel Research Institute
, 333 Bostwick Avenue, NE, Grand Rapids, Michigan 49503, USA
3VARI/SIMM Center, CAS-Key Laboratory of Receptor Research,
Shanghai Institute of Materia Medica
, Chinese Academy of Sciences, Shanghai 201203, China
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Scott B. Rothbart
Scott B. Rothbart
b)
1Center for Epigenetics,
Van Andel Research Institute
, 333 Bostwick Avenue, NE, Grand Rapids, Michigan 49503, USA
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a)
Electronic address: bradley.dickson@vai.org
J. Chem. Phys. 145, 154113 (2016)
Article history
Received:
July 22 2016
Accepted:
September 30 2016
Citation
Bradley M. Dickson, Parker W. de Waal, Zachary H. Ramjan, H. Eric Xu, Scott B. Rothbart; A fast, open source implementation of adaptive biasing potentials uncovers a ligand design strategy for the chromatin regulator BRD4. J. Chem. Phys. 21 October 2016; 145 (15): 154113. https://doi.org/10.1063/1.4964776
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