A fast, open source implementation of adaptive biasing potentials uncovers a ligand design strategy for the chromatin regulator BRD4.
作者： H. Eric Xu , H. Eric Xu , Bradley M. Dickson , Parker W. de Waal , Zachary H. Ramjan
DOI: 10.1063/1.4964776
关键词: Topology 、 Regulator 、 Druggability 、 Design strategy 、 Computer cluster 、 Molecular biophysics 、 Chromatin 、 Molecular dynamics 、 Computer science 、 Ligand (biochemistry) 、 Nanotechnology
摘要: In this communication we introduce an efficient implementation of adaptive biasing that greatly improves the speed free energy computation in molecular dynamics simulations. We investigated use accelerated simulations to inform on compound design using a recently reported and clinically relevant inhibitor chromatin regulator BRD4 (bromodomain-containing protein 4). Benchmarking our local compute cluster, achieves up 2.5 times more force calls per day than plumed2. Results five 1 μs-long are presented, which reveal conformational switch between binding competent incompetent state. Stabilization led −3 kcal/mol improvement absolute energy. These studies suggest unexplored ligand principle offer new actionable hypotheses for medicinal chemistry efforts against druggable epigenetic target class.
scitation.org
harvard.edu
aip.org 
sci-hub.st 参考文章(28)
Michael McGovern, Juan de Pablo, A boundary correction algorithm for metadynamics in multiple dimensions. Journal of Chemical Physics. ,vol. 139, pp. 084102- ,(2013) , 10.1063/1.4818153
Berk Hess, Carsten Kutzner, David van der Spoel, Erik Lindahl, GROMACS 4: Algorithms for highly efficient, load-balanced, and scalable molecular simulation Journal of Chemical Theory and Computation. ,vol. 4, pp. 435- 447 ,(2008) , 10.1021/CT700301Q
Bradley M. Dickson, Approaching a parameter-free metadynamics. Physical Review E. ,vol. 84, pp. 037701- ,(2011) , 10.1103/PHYSREVE.84.037701
Yibing Shan, Eric T. Kim, Michael P. Eastwood, Ron O. Dror, Markus A. Seeliger, David E. Shaw, How does a drug molecule find its target binding site Journal of the American Chemical Society. ,vol. 133, pp. 9181- 9183 ,(2011) , 10.1021/JA202726Y
V. Limongelli, M. Bonomi, M. Parrinello, Funnel metadynamics as accurate binding free-energy method Proceedings of the National Academy of Sciences of the United States of America. ,vol. 110, pp. 6358- 6363 ,(2013) , 10.1073/PNAS.1303186110
David E. Shaw, J.P. Grossman, Joseph A. Bank, Brannon Batson, J. Adam Butts, Jack C. Chao, Martin M. Deneroff, Ron O. Dror, Amos Even, Christopher H. Fenton, Anthony Forte, Joseph Gagliardo, Gennette Gill, Brian Greskamp, C. Richard Ho, Douglas J. Ierardi, Lev Iserovich, Jeffrey S. Kuskin, Richard H. Larson, Timothy Layman, Li-Siang Lee, Adam K. Lerer, Chester Li, Daniel Killebrew, Kenneth M. Mackenzie, Shark Yeuk-Hai Mok, Mark A. Moraes, Rolf Mueller, Lawrence J. Nociolo, Jon L. Peticolas, Terry Quan, Daniel Ramot, John K. Salmon, Daniele P. Scarpazza, U. Ben Schafer, Naseer Siddique, Christopher W. Snyder, Jochen Spengler, Ping Tak Peter Tang, Michael Theobald, Horia Toma, Brian Towles, Benjamin Vitale, Stanley C. Wang, Cliff Young, Anton 2: raising the bar for performance and programmability in a special-purpose molecular dynamics supercomputer ieee international conference on high performance computing data and analytics. pp. 41- 53 ,(2014) , 10.1109/SC.2014.9
David E. Shaw, Martin M. Deneroff, Ron O. Dror, Jeffrey S. Kuskin, Richard H. Larson, John K. Salmon, Cliff Young, Brannon Batson, Kevin J. Bowers, Jack C. Chao, Michael P. Eastwood, Joseph Gagliardo, J. P. Grossman, C. Richard Ho, Douglas J. Ierardi, István Kolossváry, John L. Klepeis, Timothy Layman, Christine McLeavey, Mark A. Moraes, Rolf Mueller, Edward C. Priest, Yibing Shan, Jochen Spengler, Michael Theobald, Brian Towles, Stanley C. Wang, Anton, a special-purpose machine for molecular dynamics simulation Communications of the ACM. ,vol. 51, pp. 91- 97 ,(2008) , 10.1145/1364782.1364802
Melinda Wenner Moyer, First drugs found to inhibit elusive cancer target. Nature Medicine. ,vol. 17, pp. 1325- 1325 ,(2011) , 10.1038/NM1111-1325
Vincent Zoete, Michel A. Cuendet, Aurélien Grosdidier, Olivier Michielin, SwissParam: a fast force field generation tool for small organic molecules. Journal of Computational Chemistry. ,vol. 32, pp. 2359- 2368 ,(2011) , 10.1002/JCC.21816
Ron O. Dror, Albert C. Pan, Daniel H. Arlow, David W. Borhani, Paul Maragakis, Yibing Shan, Huafeng Xu, David E. Shaw, Pathway and mechanism of drug binding to G-protein-coupled receptors Proceedings of the National Academy of Sciences of the United States of America. ,vol. 108, pp. 13118- 13123 ,(2011) , 10.1073/PNAS.1104614108