Hydration Structure of a Single DNA Molecule Revealed by Frequency

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The Hydration Structure of a Single DNA Molecule Revealed by FM-AFM Kfir Kuchuk, and Uri Sivan Nano Lett., Just Accepted Manuscript • DOI: 10.1021/acs.nanolett.8b00854 • Publication Date (Web): 22 Mar 2018 Downloaded from http://pubs.acs.org on March 22, 2018

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The Hydration Structure of a Single DNA Molecule Revealed by FM-AFM Kfir Kuchuk and Uri Sivan* Department of Physics and the Russell Berrie Nanotechnology Institute, Technion - Israel Institute of Technology, Haifa, 32000, Israel

Abstract: Hydration interaction shapes biomolecules and is a dominant inter-molecular force. Mapping the hydration patterns of biomolecules is therefore essential for understanding molecular processes in biology. Numerous studies have been devoted to this challenge but current methods cannot map the hydration of single biomolecules, let alone under physiological conditions. Here, we show that FM-AFM can fill this gap and generate 3D hydration maps of single DNA molecules under near-physiological conditions. Additionally, we present real space images of DNA in which the double helix is resolved with unprecedented resolution, clearly revealing individual phosphate groups along the DNA backbone. FM-AFM therefore emerges as a powerful enabling tool in the study of individual biomolecules and their hydration under physiological conditions.

Keywords: AFM, DNA, Hydration, Single Molecule Biophysics *E-mail: [email protected]. Phone number: +972-4-8293452

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The hydration of biomolecules is an integral part of their structure and function. The famous DNA double helix, for example, is stabilized by a configuration of water molecules bound to its minor groove, aptly known as the “spine of hydration"1,2, while competition between water molecules and biomolecules over interaction with DNA is known to steer biological processes3. DNA hydration has been studied extensively thus far by X-ray1,2,4 and neutron4 scattering, NMR5, terahertz6 and IR7 spectroscopies, and more8,9. All of these techniques, however, require a large number of molecules and none is capable of imaging the hydration structure of a single DNA molecule. Techniques capable of mapping water distribution along DNA are typically further limited to short specific sequences and require DNA crystallization, low temperatures, or non-physiological buffers. The hydration structure of individual DNA molecules or molecules subject to specific constraints have therefore never been reported, let alone under physiological conditions. Here, we address this challenge using frequency-modulation atomic force microscopy (FM-AFM). We demonstrate that it can not only generate unparalleled real-space images of individual DNA molecules, but also resolve the intricate 3D hydration structure around them with sub-molecular resolution, and provide estimates for the hydration strength. These results open an entirely new avenue for the study of biomolecular hydration of individual molecules under near-physiological conditions. FM-AFM emerged in recent years as a powerful tool for imaging the interface between solid surfaces and aqueous solutions. It has been used to resolve the topography and hydration structure of diverse surfaces including mica10, calcite11, perfluorodecyltrichlorosilane (FDTS) monolayer12, highly oriented pyrolytic graphite (HOPG)12,13, and lipid bilayers14 with 3D atomic resolution at room temperature. The stability and regularity of these hard, atomically flat surfaces offer ideal conditions for FM-AFM data acquisition and analysis. In contrast, biomolecules such


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as DNA are soft, relatively bulky, easily perturbed by scanning, and characterized by irregular shape and composition. Atomic resolution images of biomolecules are therefore rare, and their hydration structures have never been reported before. DNA has been imaged by AFM, with increasing success, for more than 20 years15. Recently, these efforts culminated in the observation of its major and minor grooves by several FMAFM16–18 and AM-AFM19–21 studies in near-physiological conditions. The highest resolution images published to date17 also resolved molecular corrugation due to phosphate groups along the phosphate-sugar backbone. Here, we show that FM-AFM can further resolve individual phosphate groups in ultra-high resolution 2D images and reveal the 3D hydration structure of individual DNA molecules. FM-AFM utilizes a sharp tip located at the edge of a cantilever. The cantilever is oscillated at its resonance frequency, defined by a π 2 phase-lag of the tip position relative to the driving force. Tip-sample interactions shift the cantilever resonance frequency during scanning, while the π 2 phase-lag is maintained by a feedback loop. Imaging is accomplished by enabling an additional feedback loop (z-loop) which controls the tip-sample distance by driving the sample stage so that the resonance frequency remains constant while the tip scans the surface. A 2D topography image is generated by displaying the tip-sample separation needed to maintain a preset resonance frequency across the image. A 3D resonance frequency map is generated by adding another step to the 2D topography scan. Once the z-loop reaches a set-point frequency at a certain pixel, the z-loop deactivates and the tip scans up and down from that point, generating a frequency shift vs. distance curve. The z-loop then reactivates, and the tip is moved to the next pixel. Finally, one obtains a map where each pixel in a 3D volume above the sample surface is associated with a frequency shift.


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For cantilever oscillation amplitudes much smaller than the interaction range, the frequency shift is proportional to the gradient of the total conservative force acting on the tip22. Alternatively, within the Derjaguin approximation23 the resonance frequency shift is proportional to the pressure acting on the tip apex. Structured interfacial water molecules manifest themselves as oscillations in the frequency shift vs. distance curves10. These oscillations indicate that the tip is subject to an oscillatory force as it approaches the surface and displaces ordered layers of water molecules. Clear detection of these oscillations requires cantilever oscillation amplitudes smaller than the diameter of a single water molecule, ~2.8Å. The mapping of DNA hydration structure at a sufficient signal-to-noise ratio requires an ultralow noise microscope, thorough isolation from ground vibrations, and good thermal stability. The home-built AFM24 used here had 8.5fm/√Hz optoelectronic noise and a combined mechanical, cantilever, and tracking noise below 0.1Å in the full operation bandwidth. The microscope was supplemented with an algorithm designed to optimize the FM-AFM feedback loop parameters25. While atomic resolution imaging of hard flat surfaces is more forgiving, algorithmic optimization of feedback parameters was found to be essential for obtaining high quality images and 3D hydration maps of DNA. A high resolution image of double-stranded DNA is depicted in Figure 1a together with a model that highlights the helix strands, the major and minor grooves, and the phosphate groups along the backbone. All of these features are clearly resolved in the image. Figure 1b shows, in an extended height scale, the DNA double helix and the supporting mica crystal lattice simultaneously at high resolution.


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Figure 1. (a) An ultra-high resolution image of DNA with a reference model of B-DNA. The major grooves, minor grooves and top-facing phosphates are highlighted with gray and white arrows on the model and the scan. Scale bar, 5nm. (b), Large-scale image showing both DNA and the mica lattice underneath it. The DNA backbone, showing major and minor grooves, appears black. Scale bar, 5nm. The major and minor groove widths in Figure 1 measure ~1.2nm and ~2.2nm, respectively, with variations of a few Angstroms. These values are consistent with previous crystallographic and FM-AFM data17,26. In contrast, the measured DNA diameter reaches ~5.5nm in Figure 1a compared with the actual value of ~2nm. This broadening is attributed to the finite tip width. It is 5 ACS Paragon Plus Environment

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easy to see, for example, that a 2nm diameter spherical tip would generate an image of ~6nm wide DNA, not far from the experimental value. The large height difference between the top of the DNA and the mica surface underneath it exposes the tip side to interaction with the DNA, leading to the broad border region between the mica lattice and the DNA grooves in Figure 1b (Figure S1). Conversely, when scanning along the DNA axis, where height variations are small, the interaction is confined to the sharp tip apex. We estimate the effective tip radius when scanning along the DNA axis at 1.5nm (Supporting Information). The same analysis also shows that the apparent phosphate diameter of ~10Å in Figure 1a reflects an actual diameter of ~6-8Å. The latter value implies that the backbone phosphates are hydrated27, in agreement with scattering experiments28. 3D frequency shift data, showing DNA and its hydration structure, are depicted in Figure 2. The double helix is clearly resolved and undistorted by thermal drift despite the long acquisition time of 3D maps compared to 2D images. A representative 2D cut through the 3D frequency shift map is depicted in Figure 2c. Hydration oscillations measured on top of DNA are mostly similar to those measured on top of mica (Figure 2d), notwithstanding variations in the oscillatory structure observed on both (Figure 2e). A histogram of oscillation widths measured on DNA and mica (Figure 2f) shows that the hydration layer widths are identically distributed with the mean value being approximately the diameter of a single water molecule. One interesting difference is that hydration oscillations on mica always end with a strong repulsion (e.g., gray curves in Figure 2e), indicating that the last water molecule is adjacent to the surface. Inside the DNA grooves, on the other hand, we sometimes find that the last hydration oscillation is removed from the repulsive region (black curves in Figure 2e), suggesting that the corresponding water molecules hang slightly above the surface.


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Figure 2. (a) Top view of the 2D surface of equal resonance frequency shift (300Hz) underlying the 3D scan. The 3D scan comprises 50×50 frequency shift vs distance curves. (b) 3D view of (a). (c) Frequency shift cross-section along the red dots of (a) and (b). (d) Individual frequency shift vs distance curves showing hydration oscillations. The curves, taken at the positions marked in c with matching color rectangles, are shifted vertically for clarity. (e) Individual curves, taken at the positions marked with black and gray diamonds in (a), shifted vertically for clarity. (f) Two histograms comparing hydration oscillation width distribution in curves taken on DNA and on

mica.


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Unlike 3D scans of pristine mica, which show hydration covering the entire surface10, the observed hydration of DNA is found to be concentrated in certain domains, mostly near the DNA grooves. Figure 3 depicts four consecutive 3D scans of the same section of a single DNA molecule. Red shading is applied to pixels with high hydration density (see Methods in Supporting Information for details). Some small variations are observed between the four images, as expected in high resolution imaging where tiny changes in tip structure affect the resulting image. For example, the minor groove at the bottom appears open in Figures 3a,d but partially covered by the phosphate backbone in Figures 3b,c. Notwithstanding these variations in imaging conditions, the hydration density images generally agree with each other regarding the hydrated domains of the DNA. Figures 3e, 3f depict frequency shift cross-sections taken along the solid and dashed lines in Figure 3d, respectively. The cross-section of Figure 3e, taken along the minor groove, shows clear hydration oscillations, indicating that the tip removed hydrating water molecules as it entered the groove. In contrast, the cross-section of Figure 3f shows no hydration oscillations along the phosphate backbone. The scarcity of hydration oscillations on top of phosphate groups does not necessarily imply lack of hydration. In fact, the phosphates are known to be hydrated by stronger hydrogen bonds than the grooves28 and our estimate of 6-8Å phosphate diameter (Supporting Information) is consistent with such hydration. The reason this hydration does not appear in Figure 3 is that individual frequency shift curves were deliberately limited by a 1kHz threshold to avoid DNA perturbation by the approaching tip. Hydration maps, such as Figure 3, therefore show only water molecules that are bound weakly enough to be removed by the tip without perturbing the DNA, yet tightly enough to register a hydration oscillation.

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Figure 3. (a-d) Hydration of the same section of a DNA molecule, measured in four consecutive 3D scans. (b-d) were shifted vertically with respect to (a) to align identical grooves. Pixels shaded red indicate high hydration density. Shaded pixels located to the sides of the molecule (dark blue region) have been removed for clarity. (e) Cross-section of frequency shift data along the solid line in (d) that passes through a hydrated domain in the groove showing clear hydration oscillations. (f) Cross-section of frequency shift data along the dashed line in (d) that passes through the sugar-phosphate backbone and does not show hydration oscillations.

The forces acting between the tip and the DNA, which can be calculated using frequency shift data22, provide a quantitative measure of hydration strength (Figure S4). The grooves, where hydration strength is intermediate and protein-DNA binding takes place3,29, are of particular interest. Knowledge of the hydration strength is critical to the understanding of molecular binding to DNA, a process involving displacement of hydrating water molecules. In summary, the present study paves the way for diverse research opportunities that are inaccessible to conventional methods. Examples include the hydration of specific DNA


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sequences or sections, the effects of mechanical constraints on hydration, variations in hydration in the presence of cations or other DNA binding molecules, and perhaps answering the longstanding question of which cations enter the grooves30. The same technique may apply to the study of proteins and other biomolecules hydration.

ASSOCIATED CONTENT

Supporting Information Methods, estimation of tip and phosphate radii, Figures S1-S3 (PDF) AUTHOR INFORMATION

Corresponding Author *E-mail: [email protected]

Notes The authors declare no competing financial interests. ACKNOWLEDGMENT This research was supported by the Israeli Science Foundation through Grant Number 547/17 and the single molecule ICore center of excellence, Grant Number 1902/12. REFERENCES (1)

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Hydration Structure of a Single DNA Molecule Revealed by Frequency

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