Molecular Modelling Of Dna Translocation In Bio-functionalized Nanopores With Applications In Gene Sequencing

The human genome project which was completed in 2003 took more than 12 years to complete at a cost of $2.7 billion. The advancement in technologies in the next five years led to the same feat being achieved in 5 months with a total cost of $1.5 million. Micro-fabrication technology has now made it possible miniaturize to micro- and nanofluidic devices for biochemical analysis. Solid-state nanopore based molecular analysis provides the potential to characterize and sequence DNA, based on the signature of the ionic current measured. A major challenge in using solid-state nanopores for DNA detection and sequencing is the molecular selectivity and sensitivity, and the control of DNA-nanopore interface. Presently, various approaches to modify nanopore surface properties and functionalized nanopores have been developed. However, the interaction between DNA and the bio-functionalized nanopores is still not well understood due to the small length scales of the DNA/nanopore and the dynamic nature of the translocation process. The aim of this thesis is to understand the interaction between the DNA and chemically modified nanopore surfaces. The translocation process of a DNA is analyzed by probing the DNA-nanopore interaction mechanisms through full atomistic molecular dynamics and the DNA-functionalized nanopore interaction mechanisms through coarse-grained molecular dynamics modelling. The DNA translocation dynamics through nanopores of various diameters and under various applied bias voltages are characterized. A non-linear relationship between DNA translocation speed and applied voltage is revealed. The effect of nanopore coating on DNA translocation speed is also analyzed. In particular, DNA translocation in nanopores coated with hairpin loop DNAs (HPL) and single stranded DNAs (ssDNAs) are compared. It is observed that a small effective pore diameter (EPD) provides a high confinement where the DNA translocation speed is dependent on the interaction potential, type, density of the coatings at voltages lower than 100mv/nm. Also, DNA is found to translocate in a ssDNA coated nanopore 900% faster when compared with the HPL coated nanopore mainly at a bias voltage of 0.01V, due to the less stiffness of the ssDNA as compared to the HPL. Such observations partially explain the bio-functionalized nanopore molecular selectivity mechanism. Such surface property-translocation dynamics relationship can be used for the optimal designs of future lab-on-chip molecular diagnostic devices. Furthermore, this study has the potential to enhance the understanding of a variety of ligand-receptor combinations of significant importance.