Understanding mechanisms of biological transport and signaling for nanotechnology applications.

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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.