MOLECULAR DYNAMICS SIMULATIONS OF CONFORMATIONAL DYNAMICS IN THE P38A MAP KINAS

这个子项目是许多利用资源的研究子项目之一 由NIH/NCRR资助的中心拨款提供。子项目的主要支持 而子项目的主要调查员可能是由其他来源提供的， 包括其它NIH来源。 列出的子项目总成本可能 代表子项目使用的中心基础设施的估计数量， 而不是由NCRR赠款提供给子项目或子项目工作人员的直接资金。 我们提出的工作的目的是进行四个20微秒长的分子动力学（MD）模拟的p38 a MAP激酶，在其未结合的形式（在溶液和结晶状态）和复杂的小分子抑制剂SB 203580。我们的希望是（a）彻底采样蛋白质的构象动力学，特别是其高度灵活的激活环，（B）解决现存晶体学和NMR数据之间的重要差异，（c）鉴定蛋白质中可能用于药物设计工作的潜在新结合位点，（d）确定当SB 203580配体结合时实验观察到的动力学增加的原因，最后（e）模拟晶体学家进行的配体浸泡实验，以检查扩散，（希望）SB 203580在晶体环境中的结合。所提出的模拟已经设计的目的是测量可观测值，可以验证对实验数据，而在同一时间提供根本上新的信息的构象行为的蛋白质，这是一个重要的药物靶标和一个典范的丝氨酸/苏氨酸蛋白激酶家族的成员。

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.