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Nanoscale COMMUNICATION Cite this: DOI: 10.1039/c8nr10354b Received 22nd December 2018, Accepted 19th February 2019 DOI: 10.1039/c8nr10354b rsc.li/nanoscale Measurement of nanomechanical properties of DNA molecules by PeakForce atomic force microscopy based on DNA origamiLin Li,a Ping Zhang,b,c Jiang Li, b,d Ying Wang, b,d Yuhui Wei, b,d Jun Hu, b,d Xingfei Zhou,* a,e Bingqian Xu* e and Bin Li * b,d Characterization of the stiness of thin DNA strands remains dicult. By constructing bilayer DNA molecules, we investigated their mechanical properties using AFM. Increased DNA thickness through DNA origami greatly reduced the substrate eect when measuring Youngs modulus, thus providing a more accurate picture of the inherent nanomechanical properties of DNA. The inherent nanomechanical properties of DNA play a funda- mental role in many of its biological processes, such as replica- tion, transcription, nucleosome positioning, and packaging. 1 Several advanced techniques have been employed to investi- gate the structural flexibility and elasticity of DNA due to its biological relevance. Particularly, in the past ten years, the natural tensile elasticity of DNA has been studied extensively at dierent forces in the pN range through optical tweezers and force spectroscopy. 2 In addition, understanding the response of DNA to an external compressive load is also necessary to help resolve the current controversy over the nature of struc- tural changes associated with some large-angle deformations of the double helix. 3 Furthermore, DNA-based materials such as DNA monolayers have been revealed as promising candi- dates for diverse applications in diagnosis and building nano- photonic structures. Nevertheless, the response of thin DNA strands to an external compression load still remains unclear. 4 Youngs modulus (E) is a measurement that provides a general description of a materials elasticity in terms of its stress threshold, or the extent of deformity when pressure is applied. 5 Atomic force microscopy (AFM) is a powerful tool for measuring the E value at a micro- and nanoscale for a variety of samples, such as amyloid fibrils, graphene, lipid layers, and proteins like IgM, purple membrane, etc. 6 However, a major issue of this measurement approach arises from the artificial eects of the rigid supporting surface. This makes it dicult to obtain the real elasticity from the measured data because the substrate coupling eect reduces the accuracy of the measurements and thus limits their applications for probing the stiness of small biomolecular molecules. 7 Although several improved strategies have been proposed to compensate for the changes in the elastic modulus for small objects at a micro scale, such as cells and gels, 8 it is still a great challenge to directly measure the compressive properties of the DNA molecule due to its intrinsic features, among which it is very thin and small, highly soft, and randomly coiled. Moreover, it is also dicult to de-couple the eects of the supporting sub- strates theoretically to extrapolate the real elastic modulus of the DNA. 7b To study the substrate eecton the compressive pro- perties of the DNA, here we present an alternative avenue that can directly account for the substrate eect. As indicated by Gavara et al., increasing the sample thickness is a useful strat- egy to reduce the eect of hard substrates on the measure- ments. 8a Here, we packed thin DNA strands of reasonable thickness to improve the accuracy of elastic modulus measure- ments through a novel DNA origami nanostructure. DNA origami has evolved to be a highly successful DNA self-assembly technology for creating nanostructures using DNA molecules. Typically, hundreds of short ssDNA molecules are programmed to be complementary with a single long ssDNA molecule to form simple and complex patterns. 9 In a common DNA origami structure, dsDNA molecules are arranged closely in parallel to form regular 1-, 2-, and 3-dimen- sional lattice patterns. 10 The parallel double helices form cylin- Electronic supplementary information (ESI) available. See DOI: 10.1039/ c8nr10354b These authors contributed equally. a School of Science, Ningbo University, Ningbo 315211, Zhejiang, China. E-mail: [email protected] b Division of Physical Biology & Bioimaging Center, Shanghai Synchrotron Radiation Facility, Key Laboratory of Interfacial Physics and Technology, Shanghai Institute of Applied Physics, Chinese Academy of Sciences, Shanghai 201800, China. E-mail: [email protected] c University of Chinese Academy of Sciences, Beijing 100049, China d Shanghai Advanced Research Institute, Chinese Academy of Sciences, Shanghai 201210, China e Single Molecule Study Laboratory, College of Engineering, University of Georgia, Athens, Georgia 30602, USA. E-mail: [email protected] This journal is © The Royal Society of Chemistry 2019 Nanoscale Published on 20 February 2019. Downloaded by Shanghai Institute of Applied Physics, CAS on 3/6/2019 12:42:43 AM. View Article Online View Journal

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  • Nanoscale

    COMMUNICATION

    Cite this: DOI: 10.1039/c8nr10354b

    Received 22nd December 2018,Accepted 19th February 2019

    DOI: 10.1039/c8nr10354b

    rsc.li/nanoscale

    Measurement of nanomechanical properties ofDNA molecules by PeakForce atomic forcemicroscopy based on DNA origami†

    Lin Li,‡a Ping Zhang,‡b,c Jiang Li, ‡b,d Ying Wang,b,d Yuhui Wei,b,d Jun Hu,b,d

    Xingfei Zhou,*a,e Bingqian Xu*e and Bin Li *b,d

    Characterization of the stiffness of thin DNA strands remains

    difficult. By constructing bilayer DNA molecules, we investigated

    their mechanical properties using AFM. Increased DNA thickness

    through DNA origami greatly reduced the substrate effect when

    measuring Young’s modulus, thus providing a more accurate

    picture of the inherent nanomechanical properties of DNA.

    The inherent nanomechanical properties of DNA play a funda-mental role in many of its biological processes, such as replica-tion, transcription, nucleosome positioning, and packaging.1

    Several advanced techniques have been employed to investi-gate the structural flexibility and elasticity of DNA due to itsbiological relevance. Particularly, in the past ten years, thenatural tensile elasticity of DNA has been studied extensively atdifferent forces in the pN range through optical tweezers andforce spectroscopy.2 In addition, understanding the responseof DNA to an external compressive load is also necessary tohelp resolve the current controversy over the nature of struc-tural changes associated with some large-angle deformationsof the double helix.3 Furthermore, DNA-based materials suchas DNA monolayers have been revealed as promising candi-dates for diverse applications in diagnosis and building nano-photonic structures. Nevertheless, the response of thin DNAstrands to an external compression load still remains unclear.4

    Young’s modulus (E) is a measurement that provides ageneral description of a material’s elasticity in terms of itsstress threshold, or the extent of deformity when pressure isapplied.5 Atomic force microscopy (AFM) is a powerful tool formeasuring the E value at a micro- and nanoscale for a varietyof samples, such as amyloid fibrils, graphene, lipid layers, andproteins like IgM, purple membrane, etc.6 However, a majorissue of this measurement approach arises from the artificialeffects of the rigid supporting surface. This makes it difficultto obtain the real elasticity from the measured data becausethe substrate coupling effect reduces the accuracy of themeasurements and thus limits their applications for probingthe stiffness of small biomolecular molecules.7 Althoughseveral improved strategies have been proposed to compensatefor the changes in the elastic modulus for small objects at amicro scale, such as cells and gels,8 it is still a great challengeto directly measure the compressive properties of the DNAmolecule due to its intrinsic features, among which it is verythin and small, highly soft, and randomly coiled. Moreover, itis also difficult to de-couple the effects of the supporting sub-strates theoretically to extrapolate the real elastic modulus ofthe DNA.7b

    To study the “substrate effect” on the compressive pro-perties of the DNA, here we present an alternative avenue thatcan directly account for the substrate effect. As indicated byGavara et al., increasing the sample thickness is a useful strat-egy to reduce the effect of hard substrates on the measure-ments.8a Here, we packed thin DNA strands of reasonablethickness to improve the accuracy of elastic modulus measure-ments through a novel DNA origami nanostructure.

    DNA origami has evolved to be a highly successful DNAself-assembly technology for creating nanostructures usingDNA molecules. Typically, hundreds of short ssDNA moleculesare programmed to be complementary with a single longssDNA molecule to form simple and complex patterns.9 In acommon DNA origami structure, dsDNA molecules arearranged closely in parallel to form regular 1-, 2-, and 3-dimen-sional lattice patterns.10 The parallel double helices form cylin-

    †Electronic supplementary information (ESI) available. See DOI: 10.1039/c8nr10354b‡These authors contributed equally.

    aSchool of Science, Ningbo University, Ningbo 315211, Zhejiang, China.

    E-mail: [email protected] of Physical Biology & Bioimaging Center, Shanghai Synchrotron Radiation

    Facility, Key Laboratory of Interfacial Physics and Technology, Shanghai Institute of

    Applied Physics, Chinese Academy of Sciences, Shanghai 201800, China.

    E-mail: [email protected] of Chinese Academy of Sciences, Beijing 100049, ChinadShanghai Advanced Research Institute, Chinese Academy of Sciences,

    Shanghai 201210, ChinaeSingle Molecule Study Laboratory, College of Engineering, University of Georgia,

    Athens, Georgia 30602, USA. E-mail: [email protected]

    This journal is © The Royal Society of Chemistry 2019 Nanoscale

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    www.rsc.li/nanoscalehttp://orcid.org/0000-0003-2372-6624http://orcid.org/0000-0002-8348-7445http://crossmark.crossref.org/dialog/?doi=10.1039/c8nr10354b&domain=pdf&date_stamp=2019-03-04http://dx.doi.org/10.1039/C8NR10354Bhttps://pubs.rsc.org/en/journals/journal/NR

  • ders with a diameter of ∼2 nm and a length per turn (10.67bp) of ∼3.6 nm. The constructed lattice structure is similar tothe standard 10.50 bp per turn found in B-DNA helices.Accordingly, we constructed a DNA origami bilayer (designedby Seeman et al.10g) to increase its thickness in order to probethe morphology and elasticity of DNA molecules (Fig. 1). Wecompared the compressibility of mono- and bilayer DNA origa-mis. The measured E shows that for both the mono- andbilayers, E varies with the loading force used by AFM.However, the E value of the bilayer DNA origami was greatlyreduced compared to that of the monolayer in multiple testsover a wide range of loading forces. This suggests that theeffect of the hard substrate on the E value of bilayer DNAorigami is greatly weakened as a result of increased thickness.

    To quantify the structural and mechanical propertiesof DNA origamis, AFM in PeakForce-Quantitative Nano-Mechanics (PF-QNM) was used.11 The PF-QNM enabled us tosimultaneously characterize multiple physical and chemicalproperties such as the topography, adhesion, elastic modulus,and deformation of the sample. Thus, the relevance of theheight to the deformation-related elasticity of the DNA origamicould be measured and analyzed. In addition, the compressiveelastic modulus of the DNA origami was derived by fitting theindentation curve with the Derjaguin–Muller–Toporov (DMT)model and could be extracted directly from the PF-QNMmapping AFM image at each pixel and at each applied force.6c,d

    To confirm whether the DNA molecules making up theDNA origami accurately represented the native features ofDNA, the topography of the DNA origami was analyzed(Fig. 2a). The measured dimensions of the cross-shaped DNAorigami were consistent with those of the designed structure(Fig. S1†). To be specific, the measured heights were ∼2.0 and

    ∼4.0 nm for the mono- and bilayer DNA origamis, respectively(Fig. 2b), consistent with the diameter of the DNA helices ofthe B-DNA crystal structure (2.0 ± 0.1 nm; RCSB protein databank, 1BNA). This clearly implies that the structure of thedsDNA used to construct the origami was not significantlyaffected by adsorption onto the mica surface. In contrast, thereported value of individual DNA height by AFM measurementwas approximately 0.9–1.5 nm, suggesting that the DNA ismore or less deformed by the attachment to the mica sub-strate.12 Since the 2.0 nm diameter of the DNA within the DNAorigami is more similar to the intrinsic state of the DNAdouble helix, it provides a native-like DNA state for the investi-gation of DNA in response to the deformation caused bystress. Furthermore, in terms of PF-QNM mapping images(Fig. 2c) we obtained distinct values of ∼14 and 6 MPa for theDNA origami mono- and bilayers, respectively (Fig. 2d). Toanalyze the thickness and the elastic modulus of the DNA ori-gamis, all data were extracted and plotted from the same sitesin the topographical and DMT images (Fig. 2e). A low heightcorresponded to a large elastic modulus, and vice versa(∼2.0 nm to ∼14.0 MPa and ∼4.0 nm to ∼6.0 MPa, respect-ively). Remarkably, similar results have been obtained withmultiple measurements and observed for differently shapedDNA origami nanostructures, for example, a 2-dimensional tri-angular shaped DNA origami (monolayer, designed byRothemund9) and its stacked condition where parts of two ori-gamis randomly overlapped (bilayer) on the surface (Fig. S2†).

    To quantitatively test the substrate-effect on the stiffness ofthe DNA origami, we mapped the DNA origami by PF-QNMwith different loaded peak-forces (60–160 pN) (Fig. S3†). Asexpected, we found that increased force resulted in decreasedheight and increased elastic modulus in both mono- andbilayers (Fig. 3a and b). Interestingly, at a force range of60–100 pN, little deviation in the E value was observed for thebilayers (Fig. 3c), while the measured height (Fig. 3a) remainedrelatively stable. To obtain more details, we plotted the distri-bution of the E value of the DNA origami within the peakforces at 60–100 pN (Fig. 3d). The E values of the mono- andbilayer origamis were 9.7 ± 4.9 and 5.4 ± 2.7 MPa, respectively.The bilayer had a narrow distribution of 1.0–10.2 MPa, andwas approximately half of that of the monolayer. Therefore,the measured E of the bilayer DNA origami showed less devi-ations and higher consistency, indicating a more reliableelastic modulus value for the natural DNA. We further ana-lysed the thickness dependence of the DNA’s Young’smodulus by using most of the updated bottom-effect correc-tion theory provided by Garcia et al.8c For the DNA origami,the Poisson coefficient is around 0.3. One typical corrected Evalue for both mono- and bilayers were 5.6 MPa and 4.8 MPa,respectively (Fig. S4†). The corrected results indicated that theYoung’s modulus of the DNA molecule was approximatelyindependent of the mono- and bilayers of the DNA origami.Thus we can conclude that the measured average E value of∼5 MPa in the bilayer origami is closer to the natural inherentmechanical properties of DNA, rather than the average E valueof ∼10 MPa obtained in the monolayer DNA origami.

    Fig. 1 Design and characterization of the bilayer DNA origami struc-ture. (a) Self-assembly process of DNA origami and the resulting cross-shaped DNA nanostructure. (b) Schematic representation of themeasurement of the mechanical properties of the cross-shaped DNAorigami adsorbed on a mica surface using PeakForce-QuantitativeNano-Mechanics (PF-QNM) AFM (top). A typical topographic image ofthe cross-shaped DNA origami showing its size and shape of the DNAorigami (bottom). (c) Schematic of indentations caused by forcesapplied on the DNA molecule (top). Typical forces compared to the tip–sample distance curves, by which the Young’s modulus was calculatedafter being fitted to the DMT equation (bottom).

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  • The results are substantially different from our previouslymeasured mechanical properties of individual DNA moleculeswith a load force up to 400 pN. The apparent low height wasfound to be ∼1.6 nm and the compressive elastic modulus of∼20–70 MPa in air.13 The measured stiffness on individualDNA was apparently higher than that of the molecules com-posing the DNA origami and showed a wide range of vari-ations. This was likely primarily due to the dehydration ofDNA molecules and the large loading forces.

    We also tried to put a single DNA molecule on DNA origamiin order to achieve a more accurate measurement. Therefore,we prepared a sample containing both the DNA origami andlambda DNA, a dsDNA molecule widely used in molecularbiology. Nevertheless, we failed to observe single DNA mole-cules on DNA origami probably due to the electrostaticrepulsive interaction between the DNA molecules. To furtherexplore the elastic moduli of individual DNA molecules withinthe DNA origami under the same conditions, we compared thestiffness of the DNA origami and single lambda DNA. Under aloading force of 100 pN, the measured height of the singlelambda dsDNA molecule was lower (1.6 ± 0.1 nm), and the Ewas higher (18.1 ± 4.1 MPa), compared to those of the mono-layer DNA origami (1.9 ± 0.1 nm and 9.6 ± 1.9 MPa) (Fig. S5†).These data imply that the large stiffness of single DNA mole-cules may be caused by deformation when adsorbing on themica surface.

    Obviously, our approach to measure the E value of DNAmolecules has several advantages. First, DNA origami in solu-tion has a height of ∼2 nm, which is more representative ofthe inherent mechanical properties of DNA molecules than the

    Fig. 2 PF-QNM characterization of the cross-shaped DNA origami. (a) AFM topographic images of the cross-shaped DNA origami. (b) Height profilealong the lines crossing both the mono- and bilayers of the cross-shaped DNA origami, marked by a dashed green line in (a, right). The profileshows the heights of ∼2.0 and 4.0 nm for the cross-shaped DNA origami in the mono- and bilayers, respectively. (c) DMT map corresponding to thearea in (a). (d) The E value obtained from the dashed peach line in (c, right). (e) Combined plot from (b) and (d). Monolayer ∼2.0 nm to ∼14.0 MPa(pink); bilayer: ∼4.0 nm to ∼6.0 MPa (grey).

    Fig. 3 Measured heights and E values of mono- (black color) andbilayer (red color) DNA origamis as a function of peak-force. (a) Force–height curves and (b) the force–E curves. (c) Scatter diagram of theheight–E ratio obtained from the experimental data in (a) and (b). (d)Histogram of the E values obtained from the experimental data in theforce range of 60–100 pN in (b). The solid lines represent Gaussian fitsto the data. The error bars in (a) and (b) represent the standard deviation,which was calculated from three independent experiments, N = 10. Datacollected in (c), N = 180.

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  • value shown by a single deformed DNA molecule (∼1.6 nm).Second, the increased thickness of the bilayer DNA allowed fora more accurate E measurement, as it decreased the substrate-effect. Finally, the width of the DNA origami can be pro-grammed within the range of tens to hundreds of nanometersfor any 2- or 3-dimensional DNA origami.14 In these cases, theinteraction area of the AFM probe with the surface of DNAincreases greatly, preventing the edge effect caused by the AFMprobe while scanning a narrow DNA molecule on a hard sub-strate. In other words, the AFM probe will certainly scan thesurface of the DNA, thus improving the precision of themeasurements. Therefore, measuring the DNA origami is anideal and practical strategy to measure the mechanical pro-perties of DNA molecules.

    In conclusion, we constructed a DNA origami nanostructureto increase the thickness of the DNA adsorbed onto a hardmica surface in order to reduce the substrate effect on themeasurement of DNA compressive elastic modulus by AFM.The measured E was force-dependent. We compared themeasured E of single DNA molecules, mono- and bilayer DNAorigamis, and found that the measured DNA E value showedlower loading-force-dependence, minimal deviations, andgood repeatability in the packed bilayer DNA origami. Ourstrategy improves the reliability of measuring the nanomecha-nical properties of DNA molecules. These results suggest DNAorigami is an interesting and suitable candidate for evaluatingthe elasticity of DNA molecules if multilayer DNA origamis areapplied. Since DNA origami can also be used to modify avariety of other molecules at the single-molecule level, ourstrategy also has the potential applications in studying thenatural mechanical properties of other biomolecules that arethin and soft, such as proteins, enzymes and lipids.

    Conflicts of interest

    There are no conflicts to declare.

    Acknowledgements

    The authors received funding from the National NaturalScience Foundation of China (31670871, 11474173, and11604358), the National Natural Science Foundation ofZhejiang Province (LY18A040003), the Chinese Academy ofSciences Knowledge Innovation Project (QYZDJ-SSW-SLH019),and the LU JIAXI International team program supported by theK.C. Wong Education Foundation and CAS.

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