MOLECULAR DYNAMICS STUDIES OF ALPHA CRYSTALLIN

这个子项目是许多研究子项目中利用 资源由NIH/NCRR资助的中心拨款提供。子项目和 调查员(PI)可能从NIH的另一个来源获得了主要资金， 并因此可以在其他清晰的条目中表示。列出的机构是 该中心不一定是调查人员的机构。 晶状体蛋白是哺乳动物晶状体的主要结构蛋白，由？-A和？-B两个亚基组成。除了作为结构蛋白的作用外，α-晶状体蛋白还有助于晶状体的屈光特性，并已被证明具有伴侣活性。在溶液中，它以聚集体的形式存在，分子量分布。聚集体大小的广泛分布被认为是导致蛋白质结晶失败的原因。β-晶体蛋白聚集体的计算模型和亚基之间相互作用的研究对于确定β-晶体蛋白的三级和四级结构是必不可少的，并可能为成功的结晶提供指导。我们目前的亚基模型是通过折叠识别方法建立的，然后通过分子力学程序进行修正。根据表面互补原理，用对接方法建立了β-晶体二聚体的模型，并用分子动力学程序NAMD和VMD对平衡状态下的二聚体进行了模拟。此外，还利用Ligploy程序研究了亚基之间的相互作用。初步的分子动力学研究和导向动力学模拟计算已经在该二聚体上进行了一纳秒。这些计算表明氢键和疏水相互作用在亚基结合中起着非常重要的作用；初步模型表明亚基之间的相互作用中包含Trp60 in？-B，这与以前的实验结果一致[1]。为了扩展这项工作并获得亚基相互作用的更多细节，需要对更大的-晶体蛋白聚集体和更长的模拟时间(例如1微秒)进行分子动力学研究。我们认为，NCSA TeraGrid集群是这些研究的宝贵资源。参考文献：1.McDermott，M.，Chiesa，R.，Roberts，J.E.，Dillon，J.(1991)生物化学30,8653-8660

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. ?-crystallin is the major structural protein of the mammalian lens and consists of two subunits, ?-A and ?-B. In addition to its role as a structural protein, a-crystallin contributes to the refractive properties of the lens and has been shown to exhibit chaperone activity. In solution, it exists in aggregate form with a distribution of molecular weights. This broad distribution of aggregate size is thought to be responsible for the unsuccessful attempts at crystallizing the protein. Computational modeling of ?-crystallin aggregates and studies on the interactions between subunits are essential for determining the tertiary and quaternary structures of ?-crystallin and may give guidance toward successful crystallization. Our current models for the subunits are built up by the fold recognition method and then refined by molecular mechanics programs. Models for ?-crystallin dimers are built up by the docking method according to the surface complementary principle and molecular dynamic programs NAMD and VMD are used to simulate the dimers at equilibrium. In addition, the Ligplot program is used to study the interactions between the subunits. Preliminary molecular dynamic studies and steered dynamic simulations calculations have been carried out for one nanosecond on the dimmer. These calculations indicate that hydrogen bonds and hydrophobic interactions play very important roles in subunit binding; the preliminary model indicates Trp60 in ?-B is included in the interactions between the subunits and this is in agreement with previous experimental results[1]. In order to extend this work and obtain further details on subunit interactions, molecular dynamic studies on both larger ?-crystallin aggregates and with longer simulation time, e.g. one microsecond, are needed. We believe that the NCSA Teragrid cluster is an invaluable resource for these studies. Reference: 1. McDermott, M., Chiesa, R., Roberts, J.E., Dillon, J. (1991) Biochemistry 30, 8653-8660