Understanding mechanisms of biological transport and signaling for nanotechnology applications.

活细胞的功能取决于分子进出细胞的选择性运输，以及不同细胞室之间的运输。自然界已经为这种受控运输进化了纳米级的分子“机器”，它结合了精致的选择性、敏感性和吞吐量，以及对结构破坏和环境噪音的高弹性。这些“纳米机器”参与了细胞内众多的调控和疾病过程，是新药的诱人靶点。例子包括核孔复合体、细菌中的分泌系统、线粒体通道和其他。这种生物转运体的精致选择性和坚固性启发了技术尖端的人造纳米分子分选设备的设计。许多这样的“纳米机器”的传输机制仍然受到激烈的科学辩论，但它们的动力学很难在相关的时间和长度尺度上直接通过实验获得。因此，理论建模在解决基本问题和发展纳米技术应用方面发挥着越来越重要的作用。*解开这种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，在纳米技术和纳米医学中具有深远的应用。从物理科学借鉴的方法已经对我们对这种纳米机器的理解产生了很大影响。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-并利用这些原理来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的粗粒度模型，这些模型将大量的分子细节整合为少量的粗粒度变量。在必要的情况下，这些模型会得到更详细的原子级模拟的补充。理论和计算工作是在与实验同事的密切合作下携手完成的。*在这项建议中，我们关注两个主要的生物“装置”--真核细胞的核孔复合体和细菌中的蛋白质分泌装置。我们将为这些系统建立全面的、多尺度的、物理上严格的计算模型。在对特定系统进行详细建模的同时，我们将研究在分子分类和响应性材料中应用的概念和结构相关的人造纳米设备的特异性和效率的一般原则。该研究项目将吸引高质量的学生，并将培训他们学习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.**