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Computational studies of DNA sequencing with graphene nanopores
KTH, School of Biotechnology (BIO), Theoretical Chemistry and Biology.
2014 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

    The aim of DNA sequencing is to obtain the order of DNA composition comprising the base pairs A (adenine) T (thymine), and C (cytosine) G (guanine). The fast development of DNA sequencing technology allows us to better understand the relationships among diseases, inheritance, and individuality. Solid state nanopores have been recommended as the next generation platform for DNA sequencing due to its low-cost and high-throughput. In particular, nanopores fabricated from graphene sheets are extremely thin and structurally robust and have been extensively used in DNA detection in recent years. In DNA sequencing, the translocation of a DNA molecule through a nanopore is known to be a very complicated issue and is affected by many factors, such as ion concentration, thickness of the nanopore, and the nanopore diameter. The technique of molecular dynamic simulations has been a complementary tool to study DNA translocation through nanopores.  

    In this thesis, I summarize my work of computational studies of DNA sequencing using graphene nanopores. These studies include: DNA translocation through single-layer graphene nanopores of different diameters under conditions of various ion concentrations and applied voltages; DNA translocation through multilayer graphene nanopores varied from a single to a few layers; pulling out single strand DNA molecules from small graphene nanopores of different geometries. The major contributions of this work include:

1. Effects of bias voltage on DNA translocation time were investigated leading to the insight that lower applied voltages can extend the time of DNA translocation through monolayer graphene nanopores. The effect of salt concentration on the corresponding ionic current was studied. At a low ionic concentration (< 0.3M), the current increases as DNA translocates through a nanopore. However, at a high ionic concentration (>0.5M), the current decreases as DNA translocates through the nanopore. A theoretical model was proposed to explore the relationship between the current and the occupied nanopore area. We demonstrated that the DNA translocation time can be prolonged by narrowing the diameter of a nanopore properly and the reduction of the blockade current depends on the ratio of the unoccupied nanopore area to the total nanopore area.

2.  DNA translocation through multilayer graphene nanopores was studied by molecular dynamics simulations with the aim to achieve single-base resolution. We show that the DNA translocation time can be extended by increasing the graphene layers up to a moderate number (7) and that the current in DNA translocation undergoes a stepwise change upon DNA going through an multi-layer graphene (MLG) nanopore. A model was built to account for the relationship between the current change and the unoccupied volume of the MLG nanopore. We demonstrate that the blockade current is closely related to the unoccupied volume. The dynamics of DNA translocation depends specifically on the interaction of nucleotides with the graphene sheet. Thus, our study indicates that the resolution of DNA detection can be improved by increasing the number of graphene layers in a certain range and by modifying the surface of graphene nanopores.

3. The effect of graphene nanopore geometry on DNA sequencing has been assessed by steered molecular dynamics simulations. DNA fragments including A, T, C, G and 5-methylcytosine (MC) were pulled through graphene nanopores of different geometries with diameters down to ~1nm by steered molecular dynamics simulations. We demonstrated that the bases (A, T, C, G, and MC) can be indentified in single-base resolution by the characteristic force peak values in a circular graphene nanopore but not in graphene nanopores of other geometries. Symmetric nanopores are thus better suited to DNA sequence detection via force curves than asymmetric nanopores. This implies that the graphene nanopore surface should be modified as symmetric as possible to sequence DNA by an atomic force microscope or optical tweezers. This helps us to understand low-cost and time-efficient DNA sequencing in narrow nanopores.

4. The translocation time for different nucleotides to pass through graphene nanopores with certain diameters was investigated. It was found that the translocation times are different for different bases under a low electric field. The results indicate that DNA can be sequenced by the translocation time to pass through a graphene nanopore.

5. Inspired by the structure of K+ channel proteins, a series of oxygen doped graphene nanopores of different size were designed to discriminate the transport of K+ and Na+ ions. The results indicate that the ion selectivity of such biomimetic graphene nanopores can be simply controlled by the size of the nanopore.  Compared to K+, the smaller radius of Na+ leads to a much higher free energy barrier in the nanopore of a certain size. 

Place, publisher, year, edition, pages
Stockholm: KTH Royal Institute of Technology, 2014. , 54 p.
Series
TRITA-BIO-Report, ISSN 1654-2312 ; 17
Keyword [en]
DNA sequencing; Graphene nanopore; Molecular dynamic simulation
National Category
Theoretical Chemistry
Research subject
Chemistry
Identifiers
URN: urn:nbn:se:kth:diva-157664ISBN: 987-91-7595-373-1 OAI: oai:DiVA.org:kth-157664DiVA: diva2:770952
Public defence
2014-12-18, FB42, AlbaNova Universitetscentrum,Roslagstullsbacken 21, Stockholm, 14:00 (English)
Opponent
Supervisors
Note

QC 20141212

Available from: 2014-12-12 Created: 2014-12-11 Last updated: 2014-12-12Bibliographically approved
List of papers
1. Theoretical study on key factors in DNA sequencing with graphene nanopores
Open this publication in new window or tab >>Theoretical study on key factors in DNA sequencing with graphene nanopores
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2013 (English)In: RSC Advances, ISSN 2046-2069, Vol. 3, no 7, 2445-2453 p.Article in journal (Refereed) Published
Abstract [en]

Solid-state nanopores, in particular graphene nanopores, are believed to have promising applications in DNA sequencing. Many efforts have been made in this research area, the ultimate goal is to extend the DNA translocation time and to achieve single-base resolution. Unfortunately, several factors in DNA sequencing are still not well understood. In this paper, we report a study on the effects of two main factors, the salt concentration and the bias voltage, on the corresponding ionic current. We propose a theoretical model to explore the relationship between the occupied nanopore area and the current. We demonstrate that the DNA translocation time can be prolonged by decreasing the bias voltage and by properly narrowing the nanopore diameter. We find that the reduction of the blockade current depends on the ratio of the unoccupied nanopore area to the total nanopore area.

Keyword
DNA Sequencing, DNA translocation, Ionic current, Salt concentration, Solid-state nanopore, Theoretical models, Theoretical study
National Category
Biological Sciences Chemical Sciences
Identifiers
urn:nbn:se:kth:diva-118298 (URN)10.1039/c2ra22109h (DOI)000313812400050 ()2-s2.0-84872726998 (Scopus ID)
Note

QC 20130215

Available from: 2013-02-15 Created: 2013-02-14 Last updated: 2014-12-12Bibliographically approved
2. Theoretical studies on the dynamics of DNA fragment translocation through multilayer graphene nanopores
Open this publication in new window or tab >>Theoretical studies on the dynamics of DNA fragment translocation through multilayer graphene nanopores
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2014 (English)In: RSC Advances, ISSN 2046-2069, E-ISSN 2046-2069, Vol. 4, no 92, 50494-50502 p.Article in journal (Refereed) Published
Abstract [en]

Motivated by several potential advantages over common sequencing technologies, solid-state nanopores, in particular graphene nanopores, have recently been extensively explored as biosensor materials for DNA sequencing. Studies carried out on monolayer graphene nanopores aiming at single-base resolution have recently been extended to multilayer graphene (MLG) films, indicating that MLG nanopores are superior to their monolayer counterparts for DNA sequencing. However, the underlying dynamics and current change in the DNA translocation to thread MLG nanopores remain poorly understood. In this paper, we report a molecular dynamics study of DNA passing through graphene nanopores of different layers. We show that the DNA translocation time could be extended by increasing the graphene layers up to a moderate number (7) under a high electric field and that the current in DNA translocation undergoes a stepwise change upon DNA going through an MLG nanopore. A model is built to account for the relationship between the current change and the unoccupied volume of the MLG nanopore. We demonstrate that the dynamics of DNA translocation depends specifically on the interaction of nucleotides with the graphene sheet. Thus, our study indicates that the resolution of DNA detection could be improved by increasing the number of graphene layers in a certain range and by modifying the surface of the graphene nanopores.

Keyword
DNA fragment, Multilayer graphene, Theoretical study
National Category
Other Chemistry Topics
Identifiers
urn:nbn:se:kth:diva-157252 (URN)10.1039/c4ra05909c (DOI)000344325400026 ()2-s2.0-84908101988 (Scopus ID)
Note

QC 20141208

Available from: 2014-12-08 Created: 2014-12-08 Last updated: 2017-12-05Bibliographically approved
3. Effects of Graphene Nanopore Geometry on DNA Sequencing
Open this publication in new window or tab >>Effects of Graphene Nanopore Geometry on DNA Sequencing
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2014 (English)In: Journal of Physical Chemistry Letters, ISSN 1948-7185, E-ISSN 1948-7185, Vol. 5, no 9, 1602-1607 p.Article in journal (Refereed) Published
Abstract [en]

In this Letter we assess the effect of graphene nanopore geometries on DNA sequencing by considering DNA fragments including A, T, C, G, and 5-methylcytosine (MC) pulled out of graphene nanopores of different geometries with diameters down to similar to 1 nm. Using steered molecular dynamics simulations it is demonstrated that the bases (A, T, C, G, and MC) can be indentified at single-base resolution through the characteristic peaks on the force profile in a circular graphene nanopore but not in nanopores with other asymmetric geometries. Our study suggests that the graphene nanopore surface should be modified as symmetrically as possible in order to sequence DNA by atomic force microscopy or optical tweezers.

Keyword
DNA sequencing, geometry, graphene nanopores, molecular simulation, symmetry
National Category
Physical Chemistry
Identifiers
urn:nbn:se:kth:diva-145816 (URN)10.1021/jz500498c (DOI)000335432800017 ()2-s2.0-84899877992 (Scopus ID)
Note

QC 20140602

Available from: 2014-06-02 Created: 2014-06-02 Last updated: 2017-12-05Bibliographically approved
4. Sequence dependence on DNA translocation time by graphene nanopore
Open this publication in new window or tab >>Sequence dependence on DNA translocation time by graphene nanopore
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(English)Manuscript (preprint) (Other academic)
National Category
Other Chemistry Topics
Identifiers
urn:nbn:se:kth:diva-157673 (URN)
Note

QS 2014

Available from: 2014-12-12 Created: 2014-12-12 Last updated: 2014-12-12Bibliographically approved
5. Na+ and K+ ion selectivity by size-controlled biomimetic graphene nanopores
Open this publication in new window or tab >>Na+ and K+ ion selectivity by size-controlled biomimetic graphene nanopores
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2014 (English)In: Nanoscale, ISSN 2040-3364, E-ISSN 2040-3372, Vol. 6, no 18, 10666-10672 p.Article in journal (Refereed) Published
Abstract [en]

Because biological ionic channels play a key role in cellular transport phenomena, they have attracted extensive research interest for the design of biomimetic nanopores with high permeability and selectivity in a variety of technical applications. Inspired by the structure of K+ channel proteins, we designed a series of oxygen doped graphene nanopores of different sizes by molecular dynamics simulations to discriminate between K+ and Na+ channel transport. The results from free energy calculations indicate that the ion selectivity of such biomimetic graphene nanopores can be simply controlled by the size of the nanopore; compared to K+, the smaller radius of Na+ leads to a significantly higher free energy barrier in the nanopore of a certain size. Our results suggest that graphene nanopores with a distance of about 3.9 A between two neighboring oxygen atoms could constitute a promising candidate to obtain excellent ion selectivity for Na+ and K+ ions.

Keyword
Biomimetics, Free energy, Graphene, Ions, Molecular dynamics, Oxygen, Cellular transport, Channel proteins, Free-energy calculations, High permeability, Ion selectivity, Molecular dynamics simulations, Research interests, Technical applications
National Category
Chemical Sciences
Identifiers
urn:nbn:se:kth:diva-153409 (URN)10.1039/c4nr01383b (DOI)000341020700032 ()2-s2.0-84906542603 (Scopus ID)
Note

QC 20141009

Available from: 2014-10-09 Created: 2014-10-03 Last updated: 2017-12-05Bibliographically approved

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