LARGE SCALE SIMULATIONS OF MEMBRANE CHANNELS AND TRANSPORTERS

这个子项目是许多研究子项目中的一个 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来源获得了主要资金， 因此可以在其他CRISP条目中表示。所列机构为 研究中心，而研究中心不一定是研究者所在的机构。 选择性运输物质穿过膜是活细胞的主要任务。由于细胞膜对水溶性物质扩散的疏水屏障，几乎每种化合物都进化出一种专门的蛋白质，以非常有选择性的方式促进所需底物的穿过。据估计，活细胞的一半以上的遗传物质和能量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、高等生物的生理学和医学中至关重要。选择性渗透和运输的问题显然是一个分子问题，其基本机制只能在原子分辨率下理解。膜和膜蛋白的原子模型的计算机模拟在描述与其功能相关的此类系统的结构和动力学方面已经非常成功。此外，几个膜通道和转运蛋白的原子分辨率结构已被解决。这些结构与可用的模拟方法沿着已经为我们在分子水平上研究这个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。几个膜通道和转运蛋白，建议在这个建议进行调查。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。下一个项目的主题是跨纯脂质双层的脂质介导的气体运输和气体扩散，其中将研究跨细胞膜的生理相关气体种类O2、CO2、CO和NO的运输。下一个项目将解决门控和选择性离子渗透在电压门控钾通道。最后两个项目将研究两种活跃的转运蛋白。在第一个，耦合的质子和糖的运输乳糖通透酶，最实验研究的主要促进剂超家族的成员，将进行研究的机制。第二个项目将解决BtuB运输维生素B12时内外膜之间的力传播机制。所提出的模拟研究都解决了基本的膜转运过程，是生物医学研究中最令人兴奋的问题之一。所有项目都需要与领先的实验小组密切合作，需要对大型系统进行长时间的模拟，因此只能通过国家超级计算中心提供的先进计算资源来完成。因此，它们代表了高性能计算的新机会，以推动生物医学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.