LARGE SCALE SIMULATION OF MEMBRANE CHANNELS AND TRANSPORTERS

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。 在这次更新申请中，我们要求有时间继续使用模拟方法对几种膜转运体和通道的机制进行研究。将研究几种活跃的转运蛋白，它们利用活细胞中的各种能源来发挥其功能。此外，我们还将继续研究另一种膜相关现象，即膜结合和凝血因子激活的机制，这是过去资金周期内最有成效的项目，也是UIUC 5个实验室之间的强大合作努力。事实上，所有项目都是在与领先的实验小组密切合作的情况下进行的。所有项目都处理相当缓慢的过程，因此需要长时间的模拟。此外，由于需要对在转运机制中起作用的脂类和水进行显式表示，并且由于结构的复杂性，需要模拟大分子组装。此类计算只能使用先进的TeraGrid计算资源进行。这些蛋白质的大小和功能的复杂性给计算研究带来了巨大的挑战。然而，在过去的一段时间里，我们通过发表在进展报告中的几篇论文证明，大规模的分子动力学模拟确实可以显著提高我们对这些生物分子中能量耦合和输运现象的分子机制的理解。由于篇幅有限，需要介绍6个项目，我们已将进度和初步成果的讨论完全委托给进度报告。我们在过去的资助期间对分配的广泛使用是这种生物分子系统计算需求的最有力的证据。然而，我们注意到，在过去的供资周期中，我们极有成效地利用了分配的时间，出版了创纪录数量的出版物(16份；请参阅进度报告)。我们想对拟议模拟的长度作一般性澄清，这可能被认为是一个“不合理”的方面。所有这些项目都涉及相当缓慢的生物分子过程(至少在微秒量级)。因此，从技术角度来看，即使比本申请中描述的更长数量级的模拟也很容易被证明是合理的。然而，我们认识到，目前不能完整地描述这些过程(例如，完整的运输周期)，我们只能涵盖这些过程中所涉及的一些步骤。因此，为了提供一个有希望令人满意的理由，我们几乎在所有情况下都会根据我们对相同或可比较的系统/现象的现有基准(主要是公布的)来确定拟议模拟的长度。

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. In this renewal application, we request time to continue our investigation of the mechanism of several membrane transporters and channels using simulation methodologies. Several active transporters that use various source of energy in a living cell for their function will be investigated. Furthermore, we will also continue our research on another membrane associated phenomenon, namely mechanism of membrane binding and activation of blood coagulation factors, which constitutes the most productive project over the past funding period, and a strong collaborative effort between 5 labs at UIUC. In fact, all of the projects are conducted in close collaboration with leading experimental groups. All Projects address rather slow processes, thus, requiring long simulations. Furthermore, due to the need of explicit representation of the lipid and water, which play role in the mechanism of transporters, and due to the complexity of the structure, large molecular assemblies need to be simulated. Such calculations can only be carried out with the advanced TeraGrid computational resources. The size and complexity of the function of these proteins pose a great challenge for computational studies. Over the last funding period, however, we have demonstrated through several published papers reported in the Progress Report, that large scale MD simulations can indeed significantly advance our understanding of the molecular mechanisms of energy coupling and transport phenomena in these biomolecules. Due to limited space and the need to describe 6 projects, we have delegated the progress and discussion of our preliminary results completely to the Progress Report. Our extensive use of the allocation over the past funding period is the strongest evidence for the computational demands of such biomolecular systems. We note, however, that we have used the allocated time extremely productively and produced a record number of publications (16; please see Progress Report) over the past funding cycle. We would like to give a general clarification with regard to the length of the proposed simulations, which might be perceived as an "unjustified" aspect. All of the projects address rather slow biomolecular processes (at least on the order of microsecond). As such, even orders of magnitude longer simulations than those described in this application can be easily justified from a technical point of view. However, we realize that such processes (e.g., complete transport cycle) cannot be currently described in their entirety, and we can only expect to cover some of the steps involved in such processes. Therefore, in order to provide a justification that will hopefully be satisfactory, almost in all cases we will base the length of the proposed simulations on our existing benchmarks (mostly published) of the same or comparable systems/phenomena.