LARGE SCALE SIMULATION OF MEMBRANE CHANNELS AND TRANSPORTERS

该子项目是利用 由NIH/NCRR资助的中心赠款提供的资源。子项目和 研究者（PI）可能从另一个NIH来源获得主要资金， 因此可以在其他CRISP条目中表示。列出的机构是 中心，不一定是研究者的机构。 在这个更新的应用程序中，我们要求时间继续我们的调查机制的几个膜转运蛋白和通道使用模拟方法。将研究几种在活细胞中使用各种能量源来实现其功能的主动转运蛋白。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活化的机制，这是过去资助期间最富有成效的项目，也是UIUC 5个实验室之间的强大合作。事实上，所有项目都是与领先的实验小组密切合作进行的。所有项目都涉及相当缓慢的过程，因此需要长时间的模拟。此外，由于需要明确的代表性的脂质和水，发挥作用的转运机制，并由于结构的复杂性，大分子组装需要模拟。这种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对计算研究提出了巨大的挑战。然而，在过去的资助期间，我们已经通过进展报告中报告的几篇已发表的论文证明，大规模MD模拟确实可以显着提高我们对这些生物分子中能量耦合和传输现象的分子机制的理解。由于篇幅有限，且需要描述6个项目，我们将进度和初步结果的讨论完全委托给进度报告。我们在过去的资助期间广泛使用的分配是这种生物分子系统的计算需求的最有力的证据。然而，我们注意到，我们非常有效地利用了分配的时间，在上一个供资周期内出版了创纪录数量的出版物（16份;请参见进度报告）。我们想对拟议模拟的时间长度作一个一般性的澄清，因为这可能被视为一个“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（至少在微秒级）。因此，从技术的角度来看，甚至比本申请中描述的模拟长几个数量级的模拟也可以很容易地证明是合理的。然而，我们认识到，这些过程（例如，完整的运输周期）目前无法对其进行全面描述，我们只能期望涵盖这些过程中涉及的一些步骤。因此，为了提供一个令人满意的理由，几乎在所有情况下，我们都将根据我们现有的相同或可比系统/现象的基准（大部分已发布）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.