This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Keywords: Molecular dynamics, computer simulation, proteins, large scale biomolecular simulation, cellular biology, bioengineering Abstract: Project 1: Single DNA manipulation through alpha-hemolysin channels: The principal component of the emerging high-throughput technology for sequencing DNA is alpha-hemolysin - a self-assembling toxin that, upon binding to a lipid membrane, forms a water=96filled transmembrane pore. A DNA strand driven through the pore by an electric field transiently blocks the current of ions; the level of the current blockade is indicative to the sequence of the DNA fragment confined by the pore. The key question for the development of this technology is the molecular mechanism of the current modulation by the sequences of confined DNA fragment. Using XT3 supercomputer at PSC, researches could simulated for the first time the dependence of the alpha-hemolysin conductance (blocked by DNA) on the electrolyte concentration revealing that at low salt conditions, the current is facilitated by positive charge carries only while the level of the ionic current is insensitive to the bulk concentration of the electrolyte. This discovery will help our experimental collaborators (A Meller, Harvard or Boston) U) to tailor their experimental set-up to optimize the signal to noise ratio. Project 2: Transport through Nuclear pores The nucleus of the cell is of central importance to the cell's ability to function. The nuclear pore complex is the first line of defense for the nucleus, protecting its genetic information by acting as a nuclear gateway which prevents harmful molecules from entering and exiting while simultaneously allowing good molecules to cross the nuclear envelope. We have used PSC's Cray XT3 to investigate the manner in which the nuclear pore complex achieves this selective gating. In the same spirit as our well-received work on the transporter importin-beta (Structure 13:1869-1879, 2005), we are performing molecular dynamics simulations on the transporter NTF2 to determine at the atomic level how the nuclear pore interacts with transporters and allows them passage. Previous simulations elucidated many more interactions with the nuclear pore than known about experimentally, and current simulations promise the same wealth of information for experimentalists and theoreticians working toward a solution of the nuclear gating mystery.
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