This CAREER award supports computational and theoretical research and education on translocation of polymers through nanopores. Nanopores are ubiquitous in nature and engineering. Their functionality ranges from transport of solutes in and out of a living cell to chemical and biological separation and drug delivery. This research program investigates electric field-driven transport of a prototypical polymer DNA molecule through biological and synthetic nanopores and accompanying changes in co-passing ionic current used to characterize the transport by experiment. Nanopore translocation experiments enable testing of physical models of diverse nanoscale phenomena at the single-molecule level. They provide information about nanoscale electrostatics and hydrodynamics, solvation and entropic forces, selectro-osmotic effecs, atomic-scale friction, adhesion, and conformational dynamics of biopolymers. The fundamental difficulty in interpretation of the nanopore translocation experiments is that the microscopic processes of interest are characterized indirectly, by measuring their influence on the nanopore current. In order to more fully exploit the unprecedented sensitivity of nanopore probes, a quantitative physical model is required to relate the microscopic events in the nanopore to the measured ionic current.
The PI aims to provide a comprehensive physical description of polymer transport through biological and synthetic nanopores through an innovative modeling method that combines all-atom molecular dynamics, Brownian dynamics, and multiscale simulations. This method will preserve the atomic-level information of the molecular dynamics method, while capitalizing on the computational efficiently of the Brownian dynamics and multiscale methods. The approach will exploit the thousandfold difference in the time scales of ion and polymer transport. The process of DNA transport through a nanopore will be characterized in statistical terms. The obtained ensemble of DNA conformations will be used to compute the corresponding ionic current blockades. The final step of the approach is to take into account the electro-kinetic effect that couples the ionic current to the polymer conformation. The main difference of this approach from the coarse-grained models that have been proposed to date is in preserving the all-atom information about the structure of the solute and nanopore and determining the ionic current blockade to the experimental accuracy. Combined with experiment, such predictive capability will greatly enhance utility of nanopores as tools to probe nanoscale systems and processes.
This research program could have direct impact on nanopore applications in biosensing and nanotechnology, such as instrumentation for personal genomics, nanofluidic electronics, and single molecule manipulation. The educational activities will focus on developing a laboratory course and lecture demonstrations for an undergraduate biological physics course. Another major undertaking is transforming a graduate course "Physics of Nanomachines," into a textbook, which will describe the physics of nanoscale interactions that governs operation of miniature biological, synthetic, and hybrid machines. One very specific objective of the program is to recruit a minority student to carry out the research activities. The program will provide the research community with modeling methods and tools implemented by professional programmers in the popular Open Source programs, including a set of self-contained tutorials containing all necessary instructions and examples.
NON-TECHNICAL SUMMARY:
This CAREER award supports computational and theoretical research and education to simulate long chain-like molecules being pulled through tiny holes that have diameters the size of a large molecule. Of particular interest are long chain-like molecules produced by living organisms. These are often called biopolymers. For a brief moment, the molecule is confined to the small volume defined by the tiny molecule-sized hole, also known as a nanopore, and its properties can be examined section by section. It is thought that through the process of pulling the biopolymer through the tiny hole the shape and chemical makeup of the molecular string can be determined. The PI will focus on developing a comprehensive physical description of this process using novel computational modeling methods.
The understanding that is gained could have direct impact on applications in biosensing and nanotechnology, such as sequencing DNA, future electronic devices, and single molecule manipulation. The educational activities will focus on developing a laboratory course and lecture demonstrations for an undergraduate biological physics course. Another major undertaking is transforming a graduate course "Physics of Nanomachines," into a textbook, which will describe the physics of interactions that governs operation of miniature biological, synthetic, and hybrid machines. One very specific objective of the program is to recruit a minority student to carry out the research activities. The program will provide the research community with modeling methods and tools implemented by professional programmers in the popular Open Source programs, including a set of self-contained tutorials containing all necessary instructions and examples.
