SEQUENCING DNA USING MSPA

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This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. Primary support for the subproject and the subproject's principal investigator may have been provided by other sources, including other NIH sources. The Total Cost listed for the subproject likely represents the estimated amount of Center infrastructure utilized by the subproject, not direct funding provided by the NCRR grant to the subproject or subproject staff. This project aims to dramatically accelerate the development of a low-cost technology for sequencing human genomes by genetically engineering the membrane channel MspA for nanopore sequencing applications. Using Anton, we will obtain a 50-microsecond all-atom molecular dynamics trajectory characterizing the electric field-driven permeation of a single DNA strand through MspA and the modulation of the ionic conductance of MspA associated with DNA transport. Analysis of the obtained trajectory will determine how the sequence of DNA nucleotides confined in the constriction of MspA modulates the ionic current through MspAthe physical effect used to determine the DNA sequence in experiment. Furthermore, the same MD trajectory will reveal a typical permeation pathway of a single DNA strand through MspA, which is required for further genetic engineering of MspA with the aim of reducing the velocity of DNA transport and thus detecting the DNA sequence from a simple ionic current measurement. This project is truly a once-in-a-lifetime opportunity to radically advance the key technology of the approaching era of personal genomics and medicine through high-performance computing.