Understanding mechanisms of biological transport and signaling for nanotechnology applications.

活细胞的功能取决于分子在细胞内外以及不同细胞间的选择性转运。大自然已经进化出纳米级分子“机器”来控制这种运输，它结合了精致的选择性、灵敏度和吞吐量，以及对结构损伤和环境噪声的高弹性。这些“纳米机器”参与了细胞中的许多调节和疾病过程，是新药的有吸引力的靶点。例子包括核孔复合体、细菌分泌系统、线粒体通道等。这种生物转运体的精致选择性和健壮性激发了技术前沿人工纳米分子分选装置的设计。许多这种“纳米机器”的传输机制仍然受到激烈的科学争论，但它们的动力学很难在相关的时间和长度尺度上直接实验。因此，理论建模在解决基本问题以及纳米技术应用的发展中发挥着越来越重要的作用。***揭示这些生物和人工通道的机制提出了基本的生物学和物理学问题，并在纳米技术和纳米医学中具有深远的应用。从物理科学中借鉴的方法已经对我们对这种纳米机器的理解产生了巨大的影响。我们的目标是在多个尺度上了解几个特定生物系统中的生物运输-从分子生物物理学到一般原理-并利用这些原理设计未来的技术应用。我们的方法依赖于基于非平衡统计力学和软物质物理学的粗粒度模型，这些模型将大量分子细节整合到少量粗粒度变量中。在必要的地方，这些模型被更详细的原子级模拟所补充。理论和计算工作是与实验同事密切合作进行的。***在本提案中，我们重点研究了两个主要的生物“装置”-真核细胞的核孔复合物和细菌的蛋白质分泌装置。我们将建立这些系统的综合多尺度物理严格计算模型。与具体系统的详细建模并行，我们将研究在概念和结构上相关的用于分子分选和响应材料的人工纳米器件的特异性和效率的一般原则。该研究项目将吸引高素质的学生，并将培养他们在生命系统的物理原理，实验数据分析和先进的计算方法

Functioning of living cells depends on selective transport of molecules into and out of the cell, as well as between different cellular compartments. Nature has evolved nano-scale molecular “machines” for this controlled transport that combine exquisite selectivity, sensitivity and throughput with high resilience with respect to structural damage and environmental noise. These "nano-machines" are involved in numerous regulatory and disease processes in the cell, and are attractive targets for new drugs. Examples include the Nuclear Pore Complex, secretion systems in bacteria, mitochondrial channels and others. The exquisite selectivity and robustness of such biological transporters inspire design of technologically cutting edge artificial nano-molecular sorting devices. Transport mechanisms of many of such "nano-machines" are still subject to intense scientific debate but their dynamics are hard to directly access experimentally on the relevant time and length scales. Consequently, theoretical modeling has been increasingly playing a central role in addressing the fundamental questions as well as the development of nano-technological applications. ***Unraveling the mechanisms of such biological and artificial channels poses fundamental biological and physical questions and has far-reaching applications in nano-technology and nano-medicine. Approaches borrowed from physical sciences have already made a large impact in our understanding of such nano-machines. Our goal is to understand the biological transport in several specific biological systems on multiple scales - from molecular biophysics to general principles - and leverage these principles for the design of future technological applications. Our approach relies on the coarse-grained models based on non-equilibrium statistical mechanics and soft matter physics, which consolidate the multitude of molecular detail into a small number of coarse-grained variables. Where necessary, these models are supplemented by more detailed, atomistic level simulations. The theoretical and computational work is performed hand in hand with close collaboration with experimental colleagues. ***In this proposal, we focus on two major biological "devices" - the Nuclear Pore Complex of eukaryotic cells and the protein secretion apparatus in bacteria. We will build comprehensive multi-scale physically rigorous computational models of these systems. In parallel with the detailed modeling of the specific systems, we will examine the general principles of specificity and efficiency in conceptually and structurally related artificial nano-devices for applications in molecular sorting and responsive materials. The research program will attract high quality students and will train them in physical principles of living systems, analysis of experimental data, and advanced computational methods.**