LARGE SCALE SIMULATIONS 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。 有选择地跨膜运输材料是活细胞的一项主要任务。由于细胞膜的疏水屏障防止水溶性物质的扩散，几乎每一种化合物都进化出一种特殊的蛋白质，以非常有选择性的方式促进所需底物的交叉。据估计，活细胞的遗传物质和能量的一半以上用于参与膜运输的蛋白质的生产和功能。因此，了解跨生物膜运输的分子机制在活细胞的生物学、高等生物体的生理学和医学上都是极其重要的。选择性渗透和传输的问题显然是一个分子问题，其潜在的机制只有在原子分辨率下才能理解。膜和膜蛋白的原子模型的计算机模拟已经非常成功地描述了这类系统与其功能相关的结构和动力学方面。此外，还解决了几种膜通道和转运体的原子分辨结构。这些结构以及可用的模拟方法为我们在分子水平上研究这一重要的膜蛋白家族的选择性和功能的结构基础奠定了基础。在这项建议中，建议研究几种膜通道和转运体。其中三个项目将继续研究水通道蛋白的渗透、选择性和门控机制。通道介导的气体传输和通过纯脂双层的气体扩散是下一个项目的主题，在该项目中，将研究生理上相关的气体物种O2、CO2、CO和NO通过细胞膜的传输。下一个项目将解决电压门控K通道中的选通和选择性离子渗透问题。最后两个项目将调查两个活跃的运输者。在第一个实验中，我们将研究主要促进剂超家族中被实验研究最多的成员--乳糖渗透酶中质子和糖转运的耦合机制。第二个项目将解决BtuB运输维生素B12的内膜和外膜之间的力传播机制。拟议的模拟研究都涉及基本的膜转运过程，是生物医学研究中最令人兴奋的问题之一。所有项目都是与领先的实验小组密切合作进行的，需要对大型系统进行长时间的模拟，因此，只有利用国家超级计算中心提供的先进计算资源才能完成。因此，它们代表着高性能计算的新机遇，以推动生物医学中一些最令人兴奋的领域的进步。

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. Selective transport of materials across the membrane is a major undertaking for a living cell. Due to the hydrophobic barrier of the cellular membrane against diffusion of water-soluble materials, for almost every compound a specialized protein has been evolved that facilitates the crossing of the desired substrate in a very selective manner. It is estimated that more than half of the genetic material and the energy of a living cell are used for production and function of proteins involved in membrane transport. Therefore, understanding the molecular mechanisms of traffic across biological membranes is of utmost importance in the biology of a living cell, in physiology of higher organisms, and in medicine. The problem of selective permeation and transport is clearly a molecular problem, and the underlying mechanisms can only be understood at an atomic resolution. Computer simulation of atomistic models of membranes and membrane proteins has been very successful in describing structural and dynamical aspects of such systems in relation to their function. Furthermore, atomic resolution structures of several membrane channels and transporters have been solved. These structures along with the available simulation methodologies have set the stage for us to investigate at a molecular level the structural basis of selectivity and function in this important family of membrane proteins. Several membrane channels and transporters are proposed to be investigated in this proposal. Three of the projects will continue to study the mechanisms of permeation, selectivity, and gating in aquaporins. Channel-mediated gas transport and gas diffusion across pure lipid bilayers are the subject of the next project, in which transport of physiologically relevant gas species, O2, CO2, CO, and NO, across the cellular membrane will be investigated. The next project will address gating and selective ion permeation in a voltage gated K channel. The last two projects will investigate two active transporters. In the first one, the mechanism of coupling of proton and sugar transport in lactose permease, the most experimentally investigated member of the Major Facilitator Superfamily, will be studied. The second project will address the mechanism of force propagation between the inner and outer membranes in transport of vitamin B12 by BtuB. The proposed simulation studies all address fundamental membrane transport processes, and are among the most exciting problems in biomedical research. All projects, conducted in close collaborations with leading experimental groups, require long simulations of large systems, and, thus, can only be accomplished with the advanced computational resources provided at national supercomputing centers. As such they represent new opportunities for high performance computing to drive progress in some of the most exciting areas of biomedicine.