A fast, open source implementation of adaptive biasing potentials uncovers a ligand design strategy for the chromatin regulator BRD4
文献类型：期刊论文
| 作者 | Dickson, Bradley M.2; de Waal, Parker W.3; Ramjan, Zachary H.2; Xu, H. Eric1,3 ; Rothbart, Scott B.2
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| 刊名 | JOURNAL OF CHEMICAL PHYSICS
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| 出版日期 | 2016-10-21 |
| 卷号 | 145期号:15 |
| ISSN号 | 0021-9606 |
| DOI | 10.1063/1.4964776 |
| 文献子类 | Article |
| 英文摘要 | 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 mu s-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. Published by AIP Publishing. |
| WOS关键词 | MOLECULAR-DYNAMICS SIMULATIONS ; BINDING ; TARGET ; METADYNAMICS ; EFFICIENT ; AMBER ; NAMD |
| 资助项目 | Van Andel Research Institute[00000000] ; National Institutes of Health[CA181343] |
| WOS研究方向 | Chemistry ; Physics |
| 语种 | 英语 |
| WOS记录号 | WOS:000386916500015 |
| 出版者 | AMER INST PHYSICS |
| 源URL | [http://119.78.100.183/handle/2S10ELR8/275848]  |
| 专题 | 药物靶标结构与功能中心 |
| 通讯作者 | Dickson, Bradley M. |
| 作者单位 | 1.Chinese Acad Sci, Shanghai Inst Mat Med, CAS Key Lab Receptor Res, VARI SIMM Ctr, Shanghai 201203, Peoples R China 2.Van Andel Res Inst, Ctr Epigenet, 333 Bostwick Ave NE, Grand Rapids, MI 49503 USA; 3.Van Andel Res Inst, Lab Struct Sci, 333 Bostwick Ave NE, Grand Rapids, MI 49503 USA; |
| 推荐引用方式 GB/T 7714 | Dickson, Bradley M.,de Waal, Parker W.,Ramjan, Zachary H.,et al. A fast, open source implementation of adaptive biasing potentials uncovers a ligand design strategy for the chromatin regulator BRD4[J]. JOURNAL OF CHEMICAL PHYSICS,2016,145(15). |
| APA | Dickson, Bradley M.,de Waal, Parker W.,Ramjan, Zachary H.,Xu, H. Eric,&Rothbart, Scott B..(2016).A fast, open source implementation of adaptive biasing potentials uncovers a ligand design strategy for the chromatin regulator BRD4.JOURNAL OF CHEMICAL PHYSICS,145(15). |
| MLA | Dickson, Bradley M.,et al."A fast, open source implementation of adaptive biasing potentials uncovers a ligand design strategy for the chromatin regulator BRD4".JOURNAL OF CHEMICAL PHYSICS 145.15(2016). |
入库方式： OAI收割
来源：上海药物研究所
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