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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Singh, Sunil P; Muthukumar, M (2014) Electrophoretic mobilities of counterions and a polymer in cylindrical pores. J Chem Phys 141:114901
Larkin, Joseph; Henley, Robert Y; Muthukumar, Murugappan et al. (2014) High-bandwidth protein analysis using solid-state nanopores. Biophys J 106:696-704
Jeon, Byoung-jin; Muthukumar, Murugappan (2014) Polymer capture by ?-hemolysin pore upon salt concentration gradient. J Chem Phys 140:015101
Muthukumar, M (2014) Communication: Charge, diffusion, and mobility of proteins through nanopores. J Chem Phys 141:081104
Katkar, H H; Muthukumar, M (2014) Effect of charge patterns along a solid-state nanopore on polyelectrolyte translocation. J Chem Phys 140:135102
Muthukumar, M (2014) Macromolecular mechanisms of protein translocation. Protein Pept Lett 21:209-16
Mirigian, Stephen; Muthukumar, Murugappan (2013) Kinetics of particle wrapping by a vesicle. J Chem Phys 139:044908
Muthukumar, M; Nossal, Ralph (2013) Micellization model for the polymerization of clathrin baskets. J Chem Phys 139:121928
Anderson, Brett N; Muthukumar, Murugappan; Meller, Amit (2013) pH tuning of DNA translocation time through organically functionalized nanopores. ACS Nano 7:1408-14
Mahalik, J P; Hildebrandt, B; Muthukumar, M (2013) Langevin dynamics simulation of DNA ejection from a phage. J Biol Phys 39:229-45

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