Computational Nanobiophysics: Modeling and Simulating Biomolecules in Confinement

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Current fabrication technology makes it possible to design and build devices on the nanometer scale. In fact, nanofluidic devices enable the containment of single molecules such as proteins and DNA, which are only several nanometers wide. This ability has ushered in a new era of single molecule studies. Moreover, the tight confinement of the molecules in these devices can be used to influence their configuration. For example, a DNA strand in a 10 nm wide nanotube remains extended, unlike its ball-like configuration in bulk fluid. Nanofluidic devices are thus ideal for the isolation of single biomolecules allowing them to be identified, characterized, manipulated, and even modified. Given the importance of DNA and proteins in biomedical research, nanofluidic devices promise to be central in the development of next generation medical devices, diagnostics, and therapies. In order to capitalize on these capabilities and develop applications, it is necessary to know in detail how biomolecules behave within these devices. The small length scale of the systems and short time scale of the dynamics present significant challenges for precise experimental measurements. Hence, computer simulations are an invaluable tool in probing the physics of biomolecules at the nanoscale as they can simulate the behaviour of biomolecules in nanofluidic devices at extremely high spatial and temporal resolutions even for complex systems. Our research program uses computer simulations to study biomolecules in confinement, with a focus on three particular systems. The first system is the passage of polymers such as DNA across membranes (known as translocation) through small, constricting pores (called nanopores). This process is ubiquitous in nature as it is arises whenever DNA, RNA, or proteins cross cell membranes. It is also central to a number of emerging nanotechnolgies, the most prominent of which is the use of nanopores for rapid, inexpensive sequencing of even single strands of DNA. This technology, which is the focus of the National Human Genome Research Institute's $17M DNA sequencing project, is set to revolutionize health care by greatly facilitating personalized medicine. Our second system of study is the nanopit system. In this setup, DNA is confined in a slit between two walls, where one wall is periodically etched with pits. Since DNA prefers to occupy regions of less confinement, it tends to fill the pits. Shorter polymers, which can fit into one pit, become stuck while longer polymers continue to move through the system by hopping between pits. Applications of these dynamics include sorting DNA by length and manipulating DNA into prescribed configurations (e.g., stretched between two pits). The third system is known as CLIC (Convex Lens Induced Confinement) in which a solution of DNA strands is placed between two coverslips and a convex lens is lowered onto the top coverslip, pressing down and forming a convex upper boundary. This unique setup allows for a wide range of confinements to be observed simultaneously and thus is an ideal platform for studying the fundamental properties of DNA. In each project, we will collaborate with experimental research groups. Through our collaborations, unique to each project, our detailed results will give insight into the experimental data which will in turn help refine the simulation approaches. Through this fundamental knowledge, we will propose and explore applications using nanofludics to identify, characterize, and manipulate biomolecules – such as sequencing DNA using nanopores. This technology will be part of the transformation of medical diagnostic, monitoring, and therapeutic approaches that are tailored to individual needs based on genetic make-up.