The urgent need to develop revolutionary technologies, for sequencing large DNA molecules quickly and economically, has led to many experimental strategies. Chief among these are the nanopore-based electrophoretic experiments. In these experiments, translocation of single molecules of DNA is monitored as they pass through protein channels and solid-state nanopores under an external electric field. While the results from such experiments are extremely promising towards reaching $1000 genome target, there are many puzzles and the physics of these nanoscopic systems needs to be understood from a fundamental scientific point of view. The proposed research deals with a fundamental understanding of the behavior of DNA in nanopore environments under the influence of electrical and hydrodynamic forces. We will investigate the challenges underlying several key system components in the goal of reducing the cost of sequencing mammalian-sized genomes to $1000. The major challenges deal with the predictability of capture of the target molecule at the nanopore, efficient threading into the pore, and slowing down the translocating molecule through the pore. We will use a combination of statistical mechanics theory, computer simulations, and numerical computation of coupled nonlinear equations to address polymer statistics and dynamics, electrostatics, and hydrodynamics in the phenomena of DNA translocation. The proposed research, while being generally relevant to all nanopore-based experiments, will be hinged specifically on: (a) role of hybridization in translocation through a-hemolysin, MspA, and solid-state pores, (b) enzyme-modulated DNA translocation through channels, and (c) control of capture rate and successful translocation rate of DNA in protein channels and solid-state nanopores.

Public Health Relevance

Availability of low-cost technologies for DNA sequencing is vital in identifying the origins of diseases and maintenance of public health. The proposed research addresses the challenges in several key system components in the development of genome sequencing technologies at the cost of $1000 per a mammalian-sized genome.

National Institute of Health (NIH)
National Human Genome Research Institute (NHGRI)
Research Project (R01)
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Special Emphasis Panel (ZHG1-HGR-N (M1))
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Schloss, Jeffery
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University of Massachusetts Amherst
Engineering (All Types)
Schools of Arts and Sciences
United States
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Muthukumar, M (2017) 50th Anniversary Perspective: A Perspective on Polyelectrolyte Solutions. Macromolecules 50:9528-9560
Jou, Ining; Muthukumar, Murugappan (2017) Effects of Nanopore Charge Decorations on the Translocation Dynamics of DNA. Biophys J 113:1664-1672
Bell, Nicholas A W; Muthukumar, Murugappan; Keyser, Ulrich F (2016) Translocation frequency of double-stranded DNA through a solid-state nanopore. Phys Rev E 93:022401
Muthukumar, Murugappan (2016) Ordinary-extraordinary transition in dynamics of solutions of charged macromolecules. Proc Natl Acad Sci U S A :
Shojaei, Hamid R; Muthukumar, Murugappan (2016) Translocation of an Incompressible Vesicle through a Pore. J Phys Chem B 120:6102-9
Mondal, Debasish; Muthukumar, M (2016) Stochastic resonance during a polymer translocation process. J Chem Phys 144:144901
Mondal, Debasish; Muthukumar, M (2016) Ratchet rectification effect on the translocation of a flexible polyelectrolyte chain. J Chem Phys 145:084906
Aksoyoglu, M Alphan; Podgornik, Rudolf; Bezrukov, Sergey M et al. (2016) Size-dependent forced PEG partitioning into channels: VDAC, OmpC, and ?-hemolysin. Proc Natl Acad Sci U S A 113:9003-8
Peng, B; Muthukumar, M (2015) Modeling competitive substitution in a polyelectrolyte complex. J Chem Phys 143:243133
Payet, Linda; Martinho, Marlène; Merstorf, Céline et al. (2015) Temperature Effect on Ionic Current and ssDNA Transport through Nanopores. Biophys J 109:1600-7

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