The urgent need to develop low-cost and high-quality revolutionary technologies for sequencing mammalian-sized genomes has inspired many experimental strategies. Chief among these is the nanopore-based electrophoresis. While excellent progress is continuously being made with this technique, there are many challenges in reaching the goals of very high quality sequencing and fabricating massively parallel sequencing devices. These challenges stem from the physics of nanopore-based electrophoresis of DNA which needs to be understood from a fundamental scientific point of view. The proposed research deals with fundamental understanding of the behavior of DNA in nanopore environments under the influence of electric and hydrodynamic forces, and ratcheting forces from enzymes. We will investigate the challenges underlying several key system components in the goal of reducing the cost, increasing the speed, and increasing the accuracy of sequencing mammalian-sized genomes. The major challenges deal with slowing down DNA through nanopore, effects of specific ions, conformational fluctuations of DNA, effects of flow fields arising from hydrodynamics, salt concentration gradients, and electroosmotic flow, and fluctuations in the processivity of enzymes. We will use a combination of concepts from polymer physics, statistical mechanics theory, computer simulations, and numerical computation of coupled nonlinear equations to address polyelectrolyte 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) slowing down DNA and fundamental understanding of translocation, mediated by voltage, temperature, identity and amount of electrolyte, salt concentration gradient, and patterns on pore surface, (b) controlling the stochasticity in enzyme-ratcheted translocation and fundamental understanding of coupling among fluctuations in enzyme processivity, DNA conformational fluctuations, and electrophoretic drift-diffusion, and (c) designing optimum configuration of compact arrays of thousands of nanopores for massively parallel DNA sequencing without crosstalk between the units.

Public Health Relevance

Availability of low-cost technologies for DNA sequencing with very high quality is vital in identifying the origins of diseases and maintenance of public health. The proposed research addresses the challenges in fundamental understanding of several key system components in the development of low-cost and high-quality genome sequencing technologies.

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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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
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
Aksoyoglu, M Alphan; Podgornik, Rudolf; Bezrukov, Sergey M et al. (2016) Size-dependent forced PEG partitioning into channels: VDAC, OmpC, and α-hemolysin. Proc Natl Acad Sci U S A 113:9003-8
Mondal, Debasish; Muthukumar, M (2016) Ratchet rectification effect on the translocation of a flexible polyelectrolyte chain. J Chem Phys 145:084906
Muthukumar, Murugappan (2016) Ordinary-extraordinary transition in dynamics of solutions of charged macromolecules. Proc Natl Acad Sci U S A :
Peng, B; Muthukumar, M (2015) Modeling competitive substitution in a polyelectrolyte complex. J Chem Phys 143:243133
Laohakunakorn, Nadanai; Thacker, Vivek V; Muthukumar, Murugappan et al. (2015) Electroosmotic flow reversal outside glass nanopores. Nano Lett 15:695-702
Muthukumar, M; Katkar, H H (2015) Reading nanopore clocks in single-molecule electrophoresis experiments. Biophys J 108:17-9
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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