MOLECULAR DYNAMICS SIMULATIONS OF CONFORMATIONAL DYNAMICS IN THE P38A MAP KINAS

P38A MAP KINAS 构象动力学的分子动力学模拟

• 批准号: 8364366
• 负责人: ADRIAN Hamilton ELCOCK
• 金额: $ 0.11万
• 依托单位: CARNEGIE-MELLON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-09-15 至 2013-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8364366
• 关键词: Behavior; Binding; Binding Sites; Biomedical Research; Complex; Data; Diffusion; Drug Delivery Systems; Drug Design; Environment; Family member; Funding; Grant; High Performance Computing; Ligand Binding; Ligands; Maps; Measures; Mitogen-Activated Protein Kinases; National Center for Research Resources; Principal Investigator; Protein-Serine-Threonine Kinases; Proteins; Research; Research Infrastructure; Resources; SB 203580; Sampling; Solutions; Source; Time; United States National Institutes of Health; Work; cost; flexibility; inhibitor/antagonist; molecular dynamics; research study; simulation; small molecule

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. Primary support for the subproject and the subproject's principal investigator may have been provided by other sources, including other NIH sources. The Total Cost listed for the subproject likely represents the estimated amount of Center infrastructure utilized by the subproject, not direct funding provided by the NCRR grant to the subproject or subproject staff. The purpose of our proposed work is to conduct four 20-microsecond-long molecular dynamics (MD) simulations of the p38a MAP kinase, in its unbound form (in both the solution and crystalline states) and in complex with the small-molecule inhibitor SB203580. Our hope is (a) to thoroughly sample the protein's conformational dynamics, especially those of its highly flexible activation loop, (b) to resolve an important discrepancy between the extant crystallographic and NMR data, (c) to identify potential new binding sites in the protein that might be exploited for drug design efforts, (d) to establish the causes of the increased dynamics observed experimentally when the SB203580 ligand binds, and finally (e) to mimic the ligand-soaking experiments performed by the crystallographers to examine the diffusion and (hopefully) binding of SB203580 within the crystalline environment. The proposed simulations have been devised with the aim of measuring observables that can be validated against experimental data while at the same time providing fundamentally new information on the conformational behavior of a protein that is both an important drug target and a paradigmatic member of the family of serine/threonine protein kinases.

该副本是利用资源的众多研究子项目之一 由NIH/NCRR资助的中心赠款提供。对该子弹的主要支持 而且，副投影的主要研究员可能是其他来源提供的 包括其他NIH来源。 列出的总费用可能 代表subproject使用的中心基础架构的估计量， NCRR赠款不直接向子弹或副本人员提供的直接资金。 我们提出的工作的目的是以其未结合形式（在溶液和结晶状态）和小分子抑制剂SB203580进行复杂的形式（在溶液和结晶状态下）进行四种20美动者的分子动力学（MD）模拟。 Our hope is (a) to thoroughly sample the protein's conformational dynamics, especially those of its highly flexible activation loop, (b) to resolve an important discrepancy between the extant crystallographic and NMR data, (c) to identify potential new binding sites in the protein that might be exploited for drug design efforts, (d) to establish the causes of the increased dynamics observed experimentally when the SB203580 ligand binds, and finally （e）模仿晶体学家进行的配体浸泡实验，以检查晶体环境中SB203580的扩散和（希望）结合。设计的模拟是为了测量可观察到的实验数据验证的，同时提供了有关蛋白质构象行为的根本新信息，既是重要的药物靶标，又是丝网/threonine蛋白蛋白激酶家族的范式成员。