DNA replication, packaging, and repair, which are among the most important cellular processes, are all facilitated and heavily regulated through DNA-protein interactions. Abnormal operations of protein motors that process information encoded in DNA are known causes of genetic and multifactorial deceases, cancer and are associated with aging. In collaborations with single-molecule experimentalists, this group develops computational models of exemplary protein-DNA systems to elucidate the molecular mechanisms of DNA processing machinery. The current research projects center around DNA replication. The demands of rapid but accurate duplication of a cell's genome require the cooperative operation of many proteins, which together form the replisome. Using available structural data, this group is building a computational model of the replisome that incorporates all essential components. Complementing DNA replication, DNA repair is crucial to survival of a biological organism. One of the most catastrophic forms of DNA damage is double-stranded DNA breakage, which is often repaired using, as a template, another DNA molecule of a similar nucleotide sequence. One of the projects in this area aims to determine the mechanism a cell uses to find such a similar-sequence template fragment on a very long DNA molecule. In eukaryotes, processing of information encoded in DNA is additionally complicated as DNA is wrapped around proteins into hierarchical structures. The projects in this area focus on mechanisms of remodeling DNA-protein structures and epigenetic regulation of such remodeling processes.
Research overview
Imagine assembling a few thousand marbles into a machine capable of transforming the energy of an electric field into mechanical torque at nearly 100% efficiency and lasting ten million cycles. Although marbles are not atoms, Nature has done exactly that, assembling carbon, oxygen, nitrogen, and hydrogen atoms into remarkable nanomachines. And while Nature took billions of years to transform primordial dirt into the molecular motors that power living cells, the atoms comprising present-day biomachines are no different from those found in common inorganic compounds, and they obey the same laws of physics that enable the machines's amazing properties. Understanding how the remarkable functionality of biological nanomachines comes about from the spatial arrangement of their atoms and using this knowledge to design synthetic systems that exceed in the performance of their biological counterparts is the focus of this group's research program.
Over the past years, nanopores in thin biological and synthetic membranes have emerged as a versatile new research tool for detection and manipulation of single biomolecules. In a typical setup, electric field is used to drive biomolecules through nanopores, producing electrical signals that can identify the chemical makeup of the transported molecules. Recent experimental studies have shown great potential of 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. 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, this group permitted 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. Examples of recent research projects in this area include simulations of DNA transport through graphene nanopores, engineering a biological nanopore MspA for real-time and ultra-low cost DNA sequencing and development of physical methods to slow DNA transport through solid-state nanopores.
Miniature machines captivate human imagination. From a flight of a bee to a beating of a flagellum, the ability of tiny creatures to perform seemingly impossible tasks inspire us with awe. While scaling up in size human technology is relatively straightforward, scaling down the systems and mechanisms without loosing functionality, ultimately to the molecular scale, remains a major challenge. The dominance of stochastic forces over gravity and inertia, surface effects over body forces, and granularity of conventional materials render application of macroscopic engineering principles at the nanoscale obsolete. While human efforts to engineer and build nanomachines have so far produced rather modest results, biology provides outstanding examples of what can be accomplished. This research thrust focuses on the development of synthetic analogs to landmark biomolecular machines such as autonomous nanoscale walkers, selective nanochannels gated by external stimuli, and membrane-bound energy conversion systems.