The success of contemporary medicine depends on timely identification of the underlying causes of a medical condition and on the availability of drugs and treatment procedures. Many medical conditions originate directly from processes at the molecular scale and, thus, manifest themselves in the purest form at the nanoscale. It is, therefore, not surprising that nanotechnology has become a valuable partner in the development of systems for both diagnosis and treatment of human disease. The technology driving the miniaturization of materials manufacturing has advanced to the point where it is now possible to manufacture synthetic device structures with the precision of a single nanometer, making possible direct readout of biomedical information from their carriers.
Over the past ten years, nanopores in thin biological or synthetic membranes have emerged as a versatile new research tool for detection and manipulation of single biomolecules. Recent experimental studies have shown great potential of biological nanopore systems for high-throughput real-time sequencing of DNA molecules. Extensive experimental efforts are directed toward improving sequencing fidelity, which involves design and manufacturing of synthetic nanopore sensors based on graphene membranes. Several groups have explored the prospects of using nanopore sensors for detection of proteins, drug molecules and epigenetic markers.
Nanopore sequencing of DNA using MspA. (a) Diagram of the apparatus. The two chambers of electrolyte separated by a lipid bilayer (purple) are connected only through the MspA porin (green). A DNA polymerase enzyme lodged at the top of the pore transports the DNA through the pore in a controlled manner. A transmembrane bias drives the ionic current. (b) An idealization of how the DNA sequence may be read from ionic current measurements.
Although manufacturing synthetic structures with feature size of several nanometers is possible, how these structures interact with biomolecules remains mostly uncharted territory. The watery environments necessary for biology and the function of biomolecules are incompatible with the imaging methods usually applied to the nanoscale, such as electron microscopy. Computer modeling, in particular all-atom MD simulations, have become a trusted partner in the development of nanoscale biomedical sensors, allowing one to visualize and quantify the nanoscale details of interactions between biomolecules and synthetic materials.
In the development of nanopore sequencing technology, the Center has enabled the visualization of the process of nanopore translocation and the prediction of signals that are to be used for sequencing DNA, such as ion currents. The Center has enabled modeling of the interface between biological solutions and man-made inorganic nanostructures by providing researchers with the force fields for inorganic compounds, which are compatible with the biomolecular force field used in MD simulations. The Center's researchers have pioneered modeling of electronic sensors of biomolecules, furnishing multi-scale models of metal-oxide-semiconductor structures interacting with nucleic acids and carbon nanotube sensors, and have demonstrated the utility of computer simulations for modeling transport and adsorption in nanofluidic systems.
The overarching goal of this DBP is to assist experimental scientists, through advanced simulation and analysis methods, in the development of several key nanomedicinal technologies that promise dramatic improvements in the practice of health care. The first project is a collaboration with leading experimental groups in the field of DNA nanopore sensors that aims to transform, through genetic engineering, a bacterial membrane protein into a real-time, ultra-low cost system for sequencing human DNA. The second project targets integrated lab-on-a-chip systems for massively parallel identification of molecular biomarkers using an array of solid-state nanopores. In both projects, modeling and simulations are used to optimize nanosensor systems to increase sen- sitivity of detection and explore new detection strategies, making extensive use of the Brownian dynamics software system to be implemented within TR&D3-BD.