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Adsorption mechanisms of nucleobases on the hydrated Au(111) surface Marta Rosa, Rosa Di Felice, and Stefano Corni Langmuir, Just Accepted Manuscript • DOI: 10.1021/acs.langmuir.8b00065 • Publication Date (Web): 03 May 2018 Downloaded from http://pubs.acs.org on May 5, 2018

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Adsorption mechanisms of nucleobases on the hydrated Au(111) surface Marta Rosa,∗,† Rosa Di Felice,∗,‡,¶ and Stefano Corni∗,‡,§ †Dipartimento di Scienze Chimiche, Università degli Studi di Padova, Italy ‡Center S3, CNR Institute of Nanoscience, Modena, Italy ¶Department of Physics and Astronomy, University of Southern California, Los Angeles, CA 90089, USA §Dipartimento di Scienze Chimiche, Università degli Studi di Padova, Italy E-mail: [email protected]; [email protected]; [email protected]

Abstract The solution environment is of fundamental importance in the adsorption of molecules on surfaces, a process that is strongly affected by the capability of the adsorbate to disrupt the hydration layer above the surface. Here we disclose how the presence of interface water influences the adsorption mechanism of DNA nucleobases on a gold surface. By means of metadynamics simulations, we describe the distinctive features of a complex free energy landscape for each base, which manifests activation barriers for the adsorption process. We characterize the different pathways that allow each nucleobase to overcome the barriers and be adsorbed on the surface, discussing how they influence the kinetics of adsorption of single-stranded DNA oligomers with homogeneous sequences. Our findings offer a rationale to why experimental data on the adsorption of single-stranded homo-oligonucleotides do not straightforwardly follow the thermodynamics affinity rank.

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Introduction Adsorption of biomolecules on inorganic surfaces is a fundamental process with impact in several applications of current interest, ranging from health to technology. Medical applications, for example, include the possibility to detect and recognize biomarkers, a promising approach for diagnosing and monitoring numerous diseases. 1 Furthermore, the correct understanding of the binding properties of biomolecules (e.g., proteins) on inorganic surfaces is of critical importance for applications in tissue engineering, regenerative medicine and drug delivery. 2,3 On the other hand, technological applications include for example the spreading interest in biomimetic materials, in which a deep comprehension of the interaction between biomolecular and inorganic components is needed, towards exploiting recognition and specificity properties to design new materials and devices. 4–7 While most studies of bio-inorganic systems were focused on proteins, nucleic acids also deserve attention. DNA microarrays attached to a solid surface have become quantitative methods in biology for the parallel screening of DNA-binding proteins, 8 with wide applications in genomics 9 and cancer development. 10,11 The interaction of DNA with solid surfaces is relevant for nucleic acid sequencing with nanopore technology. 12,13 It has been shown that the DNA sequence and hybridization state are fundamental determinants of both the thermodynamics and kinetics of DNA adsorption on technologically relevant surfaces such as gold. 14,15 In most useful applications, DNA-surface interactions take place in water. So far, experimental 16–22 and computational 19,22–24 studies of DNA-inorganic interactions focused on gas-phase systems, revealing the importance of dispersion (van der Waals) interactions and the occurrence of a weak chemisorption mechanism. 23–25 It is scarcely explored how these findings are affected by the presence of interface water, which has been the target of computational studies by itself. 26,27 We know that hydration is important in amino acidinorganic binding, which is strongly affected by the capability of nearby groups to disrupt the hydration layer during adsorption on gold. 28 We anticipate that it is relevant for nucleic acids adsorption as well. 2


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The adsorption of peptides on different solid surfaces has been studied by classical molecular dynamics (MD) simulations, allowing the identification of the mechanisms that determine the role of water in the adsorption process. The hydration layer was found to play a fundamental role in the adsorption, 29 with the peptides attracted to 30 or even adsorbed on 31,32 it before establishing a direct contact with the surface itself. The differential affinity of a gold-binding peptide for different gold facets, namely Au(111) and ideal and reconstructed Au(100), was found to be strongly influenced by the interaction strength between the hydration layer and the gold surface, rather than solely by the direct gold-peptide interaction. 33–35 The features of the adsorption free-energy profiles for amino acids were also observed to be strongly related to the structure of the water layer. 36 Motivated by these evidences on protein-inorganic interfaces, we undertook a study of hydrated nucleobase-gold interfaces, as a model system for nucleic acid interactions with gold surfaces and nanoparticles. By means of atomistic enhanced sampling molecular dynamics simulations in explicit water, here we show that the mechanism of adsorption and desorption of guanine (G), cytosine (C), adenine (A) and thymine (T) on Au(111) in water is delineated in a complex scenario that is nucleobase-specific. We identify the presence of activation barriers in the adsorption free energy surface (FES) of the four bases and find multiple viable adsorption pathways for each of them, whose relative importance may be tuned by the specific environment (e.g. by flanking bases in experiments with oligonucleotides). On the contrary, the gas-phase adsorption mechanism is straightforward and common to the four nucleobases. Our results on the complex landscape of the free energy surface offer an explanation to the experimental observation 14,15 that the kinetic rate of adsorption on a gold surface of different DNA sequences in solution does not reflect the strength of the nucleobase-gold interaction.

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Computational Details The calculations were performed with the Gromacs 4.5.5 MD simulation package, 37,38 complemented by the Plumed 2.0 39 plug-in for metadynamics. Trajectory analyses were performed with Gromacs tools and VMD. 40 The simulations were performed in explicit solvent using the TIP3P water model, while the AMBER99SB 41 version of the AMBER force field (FF) was used for the nucleic acids; the gold surface and its interaction with DNA bases were treated with the compatible GolDNAAMBER FF. 42 The force field was specifically parametrized against DFT calculations to describe the adsorption of DNA nucleobases on Au(111) surface. A table showing the agreement between DFT and MM calculations can be found in the SI. The volume of the simulation box was 2.60 x 2.40 x 0.44 nm3 . The box contained 5 layers of Au(111) atoms according to the slab model developed by Iori and coworkers. 43 Periodic boundary conditions (PBC) were used, with the distance between neighboring replicas larger than 20 ˚ A, which ensures negligible spurious interactions. The integration time step was 2 fs and all bonds were treated as holonomic constraints using the LINCS algorithm. The simulations were carried out in the NVT ensemble using a velocity rescaling thermostat 44 at T = 300 K. The Partiche Mesh Ewald (PME) 45 electrostatic summation was used with a real space cutoff at 1.1 nm. The force switch cutoff for Lennard-Jones nonbonded interactions was 0.9-1.1 nm. Well-tempered metadynamics 46–48 was used to sample the adsorption mechanism of the nucleobases on the gold surface. In metadynamics, the FES along few collective variables (CVs) is sampled with the aid of a biasing Gaussian potential that fills the FES local minima, thus allowing the system to overcome free-energy barriers. According to this simulation protocol, surface and bulk water conditions were sampled with statistically relevant probabilities in our work. Two CVs were used: the height of the center of mass (COM) of the nucleobase above the gold surface (d⊥ (COM-Au)) and the angle ϕ between a nucleobase axis (see red dotted segments in Figure 1) and the normal to the gold surface. The latter 4


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CV was defined differently for each nucleobase, to enable all the orientations relevant for molecule-surface interaction. The widths of the Gaussian functions were initially set to 0.1 nm and 10 degrees in the two CVs; the height was set to 2 kJ/mol. The bias potential was regularly updated every 2 ps. The well-tempered bias-factor was 30 in all the simulations. 48 The simulations were carried out until convergence of the FES was achieved. FES convergence was attained in 100 ns in the gas phase for all the four nucleobases. In water, the duration to FES convergence was 470 ns, 400 ns, 560 ns and 100 ns for G, C, A and T, respectively.

Figure 1: Chemical formulas and atom numbering for A, T, G and C. The red dotted segment in each panel identifies the axis used to define one collective variable for metadynamics. In metadynamics, the free energy is calculated as a sum of finite-width Gaussian hills. For values of the CVs in the middle of the explored CV range, hills on both sides sum up to give the final value of the free energy. Instead, this is not the case at the boundaries of the explored CV range, where in one of the two sides the hills are absent. This is an artifact of metadynamics calculations, which induces a lower value and unphysical oscillations of the free energy at the borders of bounded variables. 49 Different solutions have been proposed 5


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to solve this issue, especially in one dimension. 49–51 In this work, we are not particularly interested in free energy values at borders, because our focus is on studying the adsorption mechanism and identifying the adsorption paths along the barriers. Thus, we decided to to ignore the artificial lowering of the free energy at the edges of the CV phase space, after checking that border configurations do not correspond with a real adsorption geometry. As a memory of the artifact, we present the FES with shaded borders (Figures 2 and 3). Densities of water molecules along the direction normal to the surface (presented in Figure 4) were extracted from an unbiased dynamics of the hydrated gold surface, without adsorbed species. Densities of individual reactive atoms of the nucleobases (Figure 4) were instead obtained from the metadynamics simulations of the hydrated nucleobase/gold interfaces, using a subsets of geometries belonging to the different transition states (i.e. with CV values within a range of ± 0.04 nm, ± 2.5 deg from the transition state values).

Results Nucleobase adsorption on Au(111) in vacuo Data for the adsorption of nucleobases on Au(111) in vacuo were previously reported by us from conventional MD simulations. 23,24,42 However, metadynamics calculations allow us to get a deeper insight into the shape and topology of the FES, and to highlight the role of hydration. The preferred adsorption geometries for the four nucleobases, corresponding to the absolute minima in the free energy landscape, consist of each nucleobase parallel to the surface, slightly tilted by less than 10 degrees. d⊥ (COM-Au) is between 0.30 nm and 0.35 nm (Table 1 and Figure 2), in good agreement with the outcome of our previous unbiased MD simulations. 24 Along the ϕ CV, free energy basins are particularly broad for C and G (Figure 2), consistent with multiple competitive adsorption configurations identified from unbiased MD; 24 the free energy basins along ϕ are somewhat narrower for A and T. Figure 2 shows the free energy map in the plane of the two CVs and the preferred adsorption configurations 6


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for each nucleobase, including the energetically competitive vertical adsorption geometries for C and G. The free energy values found in the basins in the maps of Figure 2 reveal the following adsorption order, from the most to the least favorable: G < A . C < T (Table 1). For a more appropriate comparison to results from density functional theory (DFT) and MD, 24 we also computed free energy values obtained with only d⊥ (COM-Au) CV: the order obtained was the same (see SI for details). The computed relative adsorption energetics of the four bases is in agreement with desorption energies from experiments in vacuo (T < C . A < G). 17 Table 1: Energetics and structures obtained for the four nucleobabes adsorbed on the Au(111) surface in vacuo. The free energy values are relative to a reference configuration, which consists, for each molecular species, of the nucleobase immersed in water, far from the surface and transition states. Geometries labeled with a ”h” subscript correspond to horizontal adsorption geometries (molecular plane parallel to the surface plane); geometries labeled with a ”v” subscript correspond to vertical adsorption geometries (molecular plane tilted with respect to the surface plane). The computed structures are visualized in Figure 2. nucleobase label interacting free-energy d⊥ (COM-Au) atoms (kJ/mol) (nm) Adenine Ah parallel -82.9 0.33 Guanine Gh parallel -100.7 0.30 Gv1 H+NH2 -36.8 0.52 Gv2 O+N -100.7 0.40 Cytosine Ch parallel -84.6 0.33 Cv O -74.3 0.39 Thymine Th parallel -71.8 0.35

ϕ angle (degrees) 89 90 131 66 77 41 96

In summary, metadynamics simulations identify a trivial adsorption mechanism of each of the four nucleobases on Au(111) in vacuo, with the free energy value decreasing monotonically as the nucleobase approaches gold (Figure 2). No energy barrier is observed for the process and the FES maps display simple funnel-like shapes. Thus, the adsorption of DNA nucleobases on Au(111) in vacuo is an enthalphy driven process, as free energy results give the same picture as the analysis of adsorption energies. 24

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Figure 2: Two-dimensional (2D) free energy landscape for the adsorption of G, C, A and T on the Au(111) surface in vacuo. The collective variables of the metadynamics simulations are on the x axis (distance from the surface of the molecule COM) and y axis (angle between the normal to the surface and the molecular axis marked in Figure 1). Border areas in the maps are shaded because they are affected by a systematic error of metadynamics (see text for details). In the structural images, the labels “v” and “h” mark vertical and horizontal adsorption geometries, respectively; red, blue, cyan and white spheres represent O, N, C and H atoms, respectively. Nucleobase adsorption on Au(111) in water The metadynamics results for hydrated base/gold interfaces outline a substantially different picture, characterized by free energy barriers at COM distances from the surface comprised in the range 0.5-0.63 nm, depending on the specific base and the CV values. While a barrierless FES implies that the molecule can reach the final destination on the substrate irrespective of the adsorption path, the existence of a free energy barrier constrains the system to few allowed adsorption paths. We find that such adsorption paths are characterized by transition states (TS’s) that are base-specific.

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The FES maps, favorable adsorption geometries and transition states are displayed in Figure 3. In the adsorbed geometry, identified by the free energy global minimum, each nucleobase is adsorbed parallel to the surface, in a geometry equivalent to that obtained in vacuo. Also in the water environment, the molecule is slightly tilted by less than 10 degrees, because of the strong interaction between O and N atoms and the surface, which at such small distances is not screened by water molecules. The values of the free energy in the minima give the order: G < A . C < T (Table 2), which is the same as in vacuo. However, experiments on uniform sequences of single-stranded DNA (ssDNA) oligomers adsorbed on Au(111) surfaces in water give a different order for the surface coverage and adsorption affinity of the nucleobases. 14,15 In particular, competitive adsorption experiments on pairs of single-stranded homo-oligonucleotides 15 highlighted that poly(dA) exhibits an extraordinary affinity for the Au surface, while poly(dC) and poly(dG) have a very similar behavior when paired together and are always dominant when competing with poly(dT). In another study, 14 only C, A and T homo-oligonucleotides were studied: higher values of surface coverage were found for poly(dA), while smaller and similar values were found for poly(dC) and poly(dT). We hypothesize that the geometry of ssDNA oligomers and the adsorption kinetics can be at the origin of the discrepancy between these experimental results, and between them and our computational study, where only single nucleobases are adsorbed on the surface. The analysis of the nucleobase behavior at the free energy barriers, which are revealed in Figure 3, is fundamental for the comprehension of this mechanism. We scrutinize the origin of the free energy barriers, absent in vacuo, by analyzing the geometries at a d⊥ (COM-Au) value of ' 0.55 nm and at different ϕ angles. This analysis indicates that the barriers corresponds to vertical or tilted geometries, in which one or more of the atoms of the nucleobase not facing the surface are approximately at the same distance from the surface as the first hydration layer. Different geometries and interactions between the nucleobase and the surface correspond to different values of the free energy barrier, originating the different transition states. In Figure 3, the geometries of the transition

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Table 2: Energetics and structures obtained for the four nucleobabes adsorbed on the Au(111) surface in explicit water. The free energy values are relative to a reference configuration, which consists, for each molecular species, of the nucleobase immersed in water, far from the surface and transition states. Geometries labeled with a ”min” subscript correspond to free energy adsorption minima; geometries labeled with a ”ts#” subscript correspond to transition states. The computed structures are visualized in Figure 3. nucleobase

label

Adenine

Amin Ats1 Ats2 Ats3 Gmin Gts1 Gts2 Cmin Cts1 Cts2 Tmin Tts1 Tts2

Guanine

Cytosine

Thymine

interacting free-energy d⊥ (COM-Au) atoms (kJ/mol) (nm) parallel -30.6 0.33 H 11.7 0.63 N+NH2 13.5 0.59 N+NH2 12.5 0.63 parallel -40.7 0.33 N+O 4.9 0.56 H 13.9 0.6 parallel -30.0 0.29 NH2 13.6 0.5 O 12.3 0.59 parallel -20.1 0.35 O 17.5 0.58 CH3 19.8 0.55

ϕ angle (degrees) 92 152 122 47 89 77 30 83 90 28 88 148 30

states corresponding to the saddle points in the free energy surface are shown. In all these transition states, the most reactive atoms of the nucleobases, N or O, are in close contact with the surface. To further understand the role of the hydration layer, we plotted the density of water molecules in the simulation box as a function of the distance from the surface plane, superimposed with the densities of nucleobase atoms that are closest to the surface in the different transition states (Figure 4). This analysis shows that the reactive atoms are approximately at the same distance from the surface as the water first layer of solvation, competing with water molecules to interact with gold and actually waiting for some of them to desorb for the nucleobase to find a way onto the surface. The smallest value of free energy of a transition state is obtained for guanine (4.9 kJ/mol, Table 2). This geometry is close to the global minimum in the 2D map representing the free energy surface: thus, one would intuitively guess that it corresponds to a horizontal

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Figure 3: 2D free energy landscape for the adsorption of G, C, A and T on a Au(111) surface in explicit liquid water at T = 300 K. The collective variables of the metadynamics simulations are on the x axis (distance from the surface of the molecule COM) and y axis (angle between the normal to the surface and the molecular axis marked in Figure 1). Border areas in the maps are shaded because they are affected by a systematic error of metadynamics (see Computational Details section). The vertical dotted line is a guide for the eye to identify the direction along which free energy barriers were identified. In the structural images, the subscripts “min” and “ts#” mark adsorbed and transition-state configurations, respectively; red, blue, cyan and white spheres represent O, N, C and H atoms, respectively; water molecules in the first hydration layers are visualized as cyan sticks. adsorption geometry. Yet, the structure visualization in the insets of Figure 3 reveals that the transition state corresponds to a vertical adsorption configuration where both a O and a N atoms are proximal to the surface (Figure 3, Gts1 ). This is always true for the four nucleobases: the geometries corresponding to z' = 0.5 nm and ϕ = 90 deg are vertical with respect to the surface. The other free energy values for transition states are between 10 and 20 kJ/mol high (Table 2) and correspond to situations where one of the most interacting atoms (O or N) becomes proximal to the surface, being located in the place of a water molecule and dragging then the adsorption of the aromatic part of the nucleobase (Figure 11


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3). We also remark that the transition state geometry of guanine corresponding to the free energy value of 4.9 kJ/mol is characterized by a smaller distance of the O and N atoms from the surface with respect to the atom-surface distances for the other nuclobases (Figure 4). This transition state geometry, where the nucleobase strongly interacts with gold through two atoms, is particularly favored, as revealed from both the energetics and the structure.

Figure 4: Density of water molecules in the simulation box superimposed with the densities of atoms interacting with the surface in the different transition states. Blue, green, red and gray surfaces indicate the densities of water molecules, N, O and C atoms, respectively. The label indicates the nucleobase, the transition state and the interacting atoms(s) of which the density is shown in the plot. The horizontal axis reports the vertical distance from the surface plane.

Relation with experiments on homo-polynucleotides The relative adsorption behavior of the nucleobases, with a different number of transition states and different values of the free energy, may impact the adsorption of single- and 12


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double-stranded DNA molecules on gold surfaces. A further study addressing the simulation of poly-nucleotides adsorbed on gold would surely augment our knowledge of the adsorption mechanism of these systems. Nevertheless, due to the large computational effort needed, it is particularly important to gain a deep comprehension of adsorption mechanisms at the level of individual nucleobases, before tackling the more realistic systems. A preliminary comparison with experiments allows us to understand the peculiar characteristics of each nucleobase and to speculate on their adsorption mechanism, which could be useful for the study of larger systems with a careful choice of methods and collective variables. Thus, we have interpreted our data in the light of experimental data on single-stranded homo-polynucleotides, although we are aware of the limitations of the comparison of our results to experimental data. In fact, in the experiments on homo-polynucletides, adsorption is not only determined by the interaction of the nucleobases with the surface, but also by the folding topologies in solution (e.g. duplex, quadruplex) and by the presence of the backbone. The latter can strongly modify the interaction with the surface, due to its chemical nature and the structural constraints that it imposes on the nucleobase geometry, influencing the interaction among nucleobases in the strand when they are adsorbing or adsorbed on gold. Nevertheless a comparison can be explicative, particularly as experimental results often report adsorption concentrations of the system both during the initial adsorption process, where kinetics is dominant in determining the concentration ratio between the different bases, and at equilibrium. In a particular experiment, 14 for example, poly(dC) displays a higher coverage than poly(dT) in the initial stages of adsorption, similar to other measurements; 15 later in the experiment, though, the poly(dT) coverage equals and eventually overcomes that of poly(dC). After 12 hours the system is not yet at equilibrium and coverage values are still evolving. The free energy values in water at the adsorption minima for the nucleobases give a measure of what would be the relative concentrations of adsorbed molecules on the Au(111) surface at equilibrium. However, as a consequence of the complex free energy landscapes, it

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is reasonable to hypothesize that both adsorption and desorption processes, especially in the early stages, can be influenced not only by the free energy values at the minima, but also by the number of adsorption paths and the height of free energy barriers. In other words, the adsorption process is the result of an interplay between the thermodynamical driving force and the complex kinetic pathways needed to implement it. The experiments mentioned above report an extraordinary affinity of poly(dA) for the gold surface with respect to the other nucleobases, both for 5-mers 15 and 25-mers 14 strands. The reported relative affinity to poly(dC) is particularly striking. In fact, the adsorption energy and free energy values for individual adenine and cytosine bases are very similar, both theoretically (Table 2) and experimentally: 17 they do not explain such a large difference in the affinity of the two homo-polynucleotides to gold surfaces. During the adsorption process, adsorption kinetics can be influenced by the differences in molecular weights between the nucleobases, but in this case we should see a difference in the opposite direction direction, with the lighter cytosine binding faster to the surface than heavier adenine. We speculate that the large affinity difference could be a consequence of the difference in the number and geometries of transition states. From our metadynamics simulations, we found that adenine is the nucleobase with the largest number of transition states: this “polymorphism” likely confers to poly(dA) filaments flexibility and versatility during adsorption on gold, allowing poly(dA) to be adsorbed more efficiently than the other species.

Summary In conclusion, we investigated the adsorption pathways of G, C, A and T on Au(111) in explicit water by means of extensive metadynamics simulations. We calculated 2D free energy maps of the systems against two collective variables that account for the distance and orientation of the nucleobase relative to the surface. The analysis of these maps and of the trajectories reveals that the number of adsorption paths, the nature of the transition

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states and the heights of the free energy barriers to be overcome, differ significantly from one nucleobase to the other. On the contrary, gas-phase adsorption is activationless and similar for all the DNA nucleobases. We pinpoint the origin of these differences in the gold hydration layer, that can be crossed and displaced by the nucleobases in different ways, depending on which functional groups contact the layer first. The diversity of adsorption pathways in aqueous phase could not be guessed by analyzing only the adsorbed equilibrium configurations, which are very similar for all nucleobases and identical to the gas-phase adsorbed configurations. Our results show in particular that in water the kinetics of adsorption (pathways and free energy barriers) is not trivially determined by the thermodynamics (governed, roughly speaking, by the depth of the free energy wells), while this is indeed the case in the gas phase. This finding is in line with experimental results on the adsorption of single-stranded homo-oligonucleotides on gold in solution, which do not conform to the thermodynamics affinity rank.

References (1) Khatayevich, D.; Page, T.; Gresswell, C.; Hayamizu, Y.; Grady, W.; Sarikaya, M. Small 2014, 10, 1505–1513. (2) Heinz, H. Curr. Opin. Chem. Eng. 2016, 11, 34–41. (3) Coppage, R.; Slocik, J. M.; Ramezani-Dakhel, H.; Bedford, N. M.; Heinz, H.; Naik, R. R.; Knecht, M. R. Journal of the American Chemical Society 2013, 135, 11048–11054. (4) Hughes, Z. E.; Nguyen, M. A.; Li, Y.; Swihart, M. T.; Walsh, T. R.; Knecht, M. R. Nanoscale 2017, 9, 421–432.

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(5) Sarikaya, M.; Tamerler, C.; Jen, A. K.-Y.; Schulten, K.; Baneyx, F. Nature materials 2003, 2, 577. (6) Bedford, N. M.; Ramezani-Dakhel, H.; Slocik, J. M.; Briggs, B. D.; Ren, Y.; Frenkel, A. I.; Petkov, V.; Heinz, H.; Naik, R. R.; Knecht, M. R. ACS nano 2015, 9, 5082–5092. (7) Park, S. Y.; Lytton-Jean, A. K.; Lee, B.; Weigand, S.; Schatz, G. C.; Mirkin, C. A. Nature 2008, 451, 553. (8) Krylov, A. S.; Zasedateleva, O. A.; Prokopenko, D. V.; Rouviere-Yaniv, J.; Mirzabekov, A. D. Nucleic Acids Res. 2001, 29, 2654–2660. (9) Mukherjee, S.; Berger, M. F.; Jona, G.; Wang, X. S.; Muzzey, D.; Snyder, M.; Young, R. A.; Bulyk, M. L. Nature genetics 2004, 36, 1331. (10) Miller, M. B.; Tang, Y.-W. Clin. Microbiol. Rev. 2009, 22, 611–633. (11) Goodwin, S.; McPherson, J. D.; McCombie, W. R. Nat. Rev. Genet. 2016, 17, 333–351. (12) Schneider, G. F.; Dekker, C. Nat. Biotechnol. 2012, 30, 326–328. (13) Howorka, S.; Cheley, S.; Bayley, H. Nat. Biotechnol. 2001, 19, 636. (14) Wolf, L. K.; Gao, Y.; Georgiadis, R. M. Lang. 2004, 20, 3357–3361. (15) Kimura-Suda, H.; Petrovykh, D. Y.; Tarlov, M. J.; Whitman, L. J. JACS 2003, 125, 9014–9015. ¨ (16) Ostblom, M.; Liedberg, B.; Demers, L. M.; Mirkin, C. A. J. Phys. Chem. B 2005, 109, 15150–15160. ¨ (17) Demers, L. M.; Ostblom, M.; Zhang, H.; Jang, N.-H.; Liedberg, B.; Mirkin, C. A. JACS 2002, 124, 11248–11249.

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Langmuir 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

(18) Kelly, R. E.; Xu, W.; Lukas, M.; Otero, R.; Mura, M.; Lee, Y.-J.; Lægsgaard, E.; Stensgaard, I.; Kantorovich, L. N.; Besenbacher, F. Small 2008, 4, 1494–1500. (19) Lukas, M.; Kelly, R. E.; Kantorovich, L. N.; Otero, R.; Xu, W.; Laegsgaard, E.; Stensgaard, I.; Besenbacher, F. J. Chem. Phys. 2009, 130, 024705. (20) Xu, W.; Kelly, R. E.; Gersen, H.; Lægsgaard, E.; Stensgaard, I.; Kantorovich, L. N.; Besenbacher, F. Small 2009, 5, 1952–1956. (21) Xu, W.; EA Kelly, R.; Otero, R.; Schöck, M.; Lægsgaard, E.; Stensgaard, I.; Kantorovich, L. N.; Besenbacher, F. Small 2007, 3, 2011–2014. (22) Kelly, R. E.; Lukas, M.; Kantorovich, L. N.; Otero, R.; Xu, W.; Mura, M.; Lægsgaard, E.; Stensgaard, I.; Besenbacher, F. J. Chem. Phys. 2008, 129, 184707. (23) Rosa, M.; Corni, S.; Di Felice, R. J. Phys. Chem. C 2012, 116, 21366–21373. (24) Rosa, M.; Corni, S.; Di Felice, R. J. Chem. Theo. Comp. 2013, 9, 4552–4561. (25) Rosa, M.; Corni, S.; Di Felice, R. Phys. Rev. B 2014, 90, 125448. (26) Cicero, G.; Calzolari, A.; Corni, S.; Catellani, A. The Journal of Physical Chemistry Letters 2011, 2, 2582–2586. (27) Huzayyin, A.; Chang, J. H.; Lian, K.; Dawson, F. The Journal of Physical Chemistry C 2014, 118, 3459–3470. (28) Maier, G. P.; Rapp, M. V.; Waite, J. H.; Israelachvili, J. N.; Butler, A. Science 2015, 349, 628–632. (29) Schneider, J.; Colombi Ciacchi, L. JACS 2012, 134, 2407–2413. (30) Skelton, A. A.; Liang, T.; Walsh, T. R. ACS applied materials & interfaces 2009, 1, 1482–1491.

17


Page 22 of 25

Page 23 of 25 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

Langmuir

(31) Penna, M. J.; Mijajlovic, M.; Biggs, M. J. 2014, (32) Bellucci, L.; Bussi, G.; Di Felice, R.; Corni, S. Nanoscale 2017, 9, 2279–2290. (33) Wright, L. B.; Rodger, P. M.; Corni, S.; Walsh, T. R. J. Chem. Theo. Comp. 2013, 9, 1616–1630. (34) Wright, L. B.; Rodger, P. M.; Walsh, T. R.; Corni, S. J. Phys. Chem. C 2013, 117, 24292–24306. (35) Wright, L. B.; Rodger, P. M.; Walsh, T. R. Langmuir 2014, 30, 15171–15180. (36) Hoefling, M.; Iori, F.; Corni, S.; Gottschalk, K.-E. Langmuir 2010, 26, 8347–8351. (37) Hess, B.; Kutzner, C.; Van Der Spoel, D.; Lindahl, E. J. Chem. Theo. Comp. 2008, 4, 435–447. (38) Van Der Spoel, D.; Lindahl, E.; Hess, B.; Groenhof, G.; Mark, A. E.; Berendsen, H. J. J. Comp. Chem. 2005, 26, 1701–1718. (39) Tribello, G. A.; Bonomi, M.; Branduardi, D.; Camilloni, C.; Bussi, G. Comput. Phys. Commun 2014, 185, 604–613. (40) Humphrey, W.; Dalke, A.; Schulten, K. J. Mol. Graph. 1996, 14, 33–38. (41) Hornak, V.; Abel, R.; Okur, A.; Strockbine, B.; Roitberg, A.; Simmerling, C. Proteins: Structure, Function, and Bioinformatics 2006, 65, 712–725. (42) Rosa, M.; Corni, S.; Di Felice, R. J. Chem. Theo. Comp. 2014, 10, 1707–1716. (43) Iori, F.; Di Felice, R.; Molinari, E.; Corni, S. J. Comp. Chem. 2009, 30, 1465–1476. (44) Bussi, G.; Donadio, D.; Parrinello, M. J. Chem. Phys. 2007, 126, 014101. (45) Essmann, U.; Perera, L.; Berkowitz, M. L.; Darden, T.; Lee, H.; Pedersen, L. G. J. Chem. Phys. 1995, 103, 8577–8593. 18


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(46) Laio, A.; Parrinello, M. Proc. Natl. Acad. Sci. 2002, 99, 12562–12566. (47) Laio, A.; Gervasio, F. L. Rep. Prog. Phys. 2008, 71, 126601. (48) Barducci, A.; Bussi, G.; Parrinello, M. Phys. Rev. Lett. 2008, 100, 020603. (49) McGovern, M.; de Pablo, J. J. Chem. Phys. 2013, 139, 084102. (50) Baftizadeh, F.; Cossio, P.; Pietrucci, F.; Laio, A. Curr. Phys. Chem. 2012, 2, 79–91. (51) Crespo, Y.; Marinelli, F.; Pietrucci, F.; Laio, A. Phys. Rev. E 2010, 81, 055701.

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