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    DNA origami: Deformable material with programmable electrical properties
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    Molecular gymnastics of DNA strands on charged graphene
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    DNA self-assembles into long end-to-end aggregates
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    MD provides structural model and mechanical properties of a complete microtubule
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    A coarse-grained model captures the atomic structure of single-stranded DNA
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    Structure and dynamics of DNA origami determined through molecular dynamics simulations

Trapping double-stranded DNA in a solid-state nanopore

The image of the double helix of DNA has become an icon of biotechnology and genetics. However, this double helix is more than just an aesthetically pleasing image: it gives double-stranded DNA peculiar mechanical properties that are pertinent to biology and biotechnology. We have previously shown that molecules of double-stranded DNA can be electrically driven through tiny pores smaller in diameter than the double helix. How is this possible? Our computer simulations show that the DNA double helix stretches and distorts as it passes through a pore smaller than itself—a situation somewhat like forcing a drinking straw through the small hole in a drink box. With this knowledge, the researchers in the Timp and Aksimentiev groups have invented a method to trap DNA by driving the molecule into the pore using a strong electric force and then reducing the electric force while the DNA is still in the pore. Using molecular dynamics simulations, we have examined the process of trapping a DNA double helix in atomic detail, providing our experimental collaborators with the estimates of the forces and time scales involved. Using a special purpose electric circuit, the researchers in the Timp group have demonstrated the trap machanism in practice. The results of this study suggest the possibility of controlling the motion of double-stranded DNA through a solid-state nanopore. Such control could facilitate nanopore sequencing, which has the potential to reduce the cost of DNA sequencing to the extent that you and your doctor could make medical decisions based on the unique information in your genome. This work is described in a report that appeared in Nanotechnology.

Sequencing DNA using a nanopore capacitor

High-throughput technology for sequencing DNA has already provided invaluable information about the organization of the human genome and the common variations of the genome sequence among groups of individuals. To date, however, the high cost of whole genome-sequencing limits widespread use of this method in basic research and personal medicine. Using nanopores in synthetic silicon membranes for sequencing DNA can dramatic reduce the sequencing costs, as they enable, in principle, direct read out of the nucleotide sequence from the DNA strand via electric measurement. Although technology for manufacturing nanopores and using them for detecting single DNA molecules have already been demonstrated, a method for determining the DNA sequence with a single-nucleotide precision was lacking. In this study, we investigated the feasibility of sequencing DNA using an electric field in a nanopore that alternates periodically in time. Through molecular dynamics simulations, we demonstrated that back-and-forth motion of DNA in a 1-nm-diameter pore has a sequence-specific hysteresis that results in a detectable change of the electrostatic potential at the electrodes of the nanopore capacitor and in a sequence-specific drift of the DNA strand through the pore under an oscillating bias. On the basis of these observations, we proposed a method for detecting DNA sequences by modulating the duty cycle of the periodic alternating potential. When implemented technologically, this method can lead to major advances in healthcare, as it will make personal genomics an affordable reality. This study has been described in a report published in Nano Letters.

Ion conductance properties of the phospholamban pentamer

Muscle cells respond to external nerve stimuli by releasing Ca2+ signaling ions from a storage organelle called the sarcoplasmic reticulum (SR). The Ca2+ exposes myosin binding sites on actin filaments, which allows myosin to ratchet along actin and causes the cell to contract. In order for muscle fibers to relax, Ca2+ must be transported from the cytoplasm back to the SR. The Ca2+-ATPase resides in the membrane of the SR and transports two Ca2+ ions against a concentration gradient by using energy of ATP hydrolysis. The uptake of Ca2+ by Ca2+-ATPase is regulated by the membrane protein phospholamban (PLN), which acts as an inhibitor. Although more than 75% of PLN in a lipid bilayer membrane is pentameric, the only known function of PLN, i.e. Ca2+-ATPase inhibition, involves a PLN monomer and not a pentamer. Using all-atom and coarse grained molecular dynamics simulations, we investigated structural dynamics and conductance properties of the recently reported NMR structure of the PLN pentamer. Our simulations demonstrated that, in a lipid bilayer membrane or a detergent micelle, the cytopasmic part of the pentamer undergoes large structural fluctuations while the transmembrane part of the pentamer shrinks and becomes asymmetric. Bound states between neighboring cytoplasmic helices were observed suggesting that the cytoplasmic region may facilitate recognition between oligomerizing protomers. Using steered molecular dynamics simulations, we investigated the feasibility of ion conductance through the pore of a PLN pentamer. The resulting approximate potentials of mean force indicate that the PLN pentamer is unlikely to function as an ion channel. This work is described in a report that appeared in Biophysical Journal.

Molecular dynamics reveals effective interaction between parallel DNA

DNA is so famously known as the carrier of genetic information that the structural and dynamical aspects of the molecule are often neglected. However, most cellular processes that involve DNA cannot be understood without consideration of its interactions with other DNA and proteins. Such interactions can give rise self-assembled structures, for example DNA supercoils, which we strive to understand using a bottom-up approach by examining the most basic constituents of a larger more complex system. Thus, in collaboration with the groups of Ralf Seidel at the University of Technology in Dresden and Gero Wedemann at the University of Applied Sciences Stralsund, we have examined the interactions between DNA helices in plectonemic supercoils using magnetic tweezers, coarse-grained Monte Carlo and atomistic molecular dynamics simulations. Building on our previous work, our group characterized the effective forces between parallel DNA in monovalent electrolytes at different ion concentrations. Our simulations revealed that the force between the DNA molecules is much smaller than that predicted by the Debye-Hückel cylinder model and that continuum models fail to describe DNA electrostatics. We further demonstrate that DNA-DNA interactions in monovalent electrolyte are well described using this simple cylinder model provided a significant charge adaptation factor is employed. Application of this model in coarse-grained Monte Carlo simulations provided results in excellent agreement with experimentally obtained results over a wide range of concentrations. This work is described in a report that appeared in Physical Review Letters.

Electrostatic Tweezers

Understanding how protein machinery of a biological cell packages, copies, and transcribes the encyclopedic information encoded in the genome requires the capability of applying forces like those in nature in a laboratory dish. Although optical traps, magnetic beads and an atomic force microscope can be used to apply forces to individual biomolecules, these tools employ tethers to transmit force from micron-size objects to the biomolecules of interest and generally have low throughput. The laboratories of Gregory Timp (ECE) and Aleksei Aksimentiev (Physics) at the University of Illinois, Urbana-Champaign have recently demonstrated a new tool for single molecule manipulation that obviates the use of tethers and offers high throughput. In this method the gradient of the electrostatic potential is used to capture single DNA molecules and associated proteins in a solid-state nanopore. Once DNA is loaded into a nanopore, the electrostatic field is used to rupture the DNA-protein complex. Using a nanopore as electrostatic tweezers, the researchers have analyzed the forces binding a protein to a specific nucleotide sequence of a DNA molecule. Molecular dynamics simulations validated the electrostatic tweezers mechanism and provided accurate estimates of the forces involved. This study has been described in two reports published in Nano Letters and Nucleic Acids Research.