On the Mechanism of Protein Adsorption onto Hydroxylated and

Aug 10, 2010 - Modeling the Interaction between Integrin-Binding Peptide (RGD) and Rutile Surface: The Effect of Cation Mediation on Asp Adsorption. C...
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On the Mechanism of Protein Adsorption onto Hydroxylated and Nonhydroxylated TiO2 Surfaces Yu Kang,†,‡ Xin Li,† Yaoquan Tu,§ Qi Wang,‡ and Hans Ågren*,† Department of Theoretical Chemistry, School of Biotechnology, Royal Institute of Technology, S-106 91 Stockholm, Sweden, Department of Chemistry, Zhejiang UniVersity, Hangzhou 310027, People’s Republic of China, and Biophysical Chemistry, School of Science and Technology, ¨ rebro UniVersity, 701 82 O ¨ rebro, Sweden O ReceiVed: April 25, 2010; ReVised Manuscript ReceiVed: July 6, 2010

Protein adsorption onto implant surfaces is of great importance for the regulation of implant bioactivity. Surface modification of implants is a promising way in the molecular design of biocompatible materials against nonspecific adsorption of proteins. On the basis of these fundamental facts, we focus in this work on the different behavior of protein adsorption on hydroxylated and nonhydroxylated rutile TiO2 (110) surfaces through molecular dynamics simulations. Our investigation indicates that the distribution of the water molecules at the interface induced by the surface modification plays an important role in the protein adsorption. The surface with modified hydroxyl groups was observed to have much greater affinity to the protein, as reflected by the larger protein-surface electrostatic interaction and by the larger amount of adsorbed residues. The highly ordered structure of the modified hydroxyl groups on the hydroxylated surface diminishes the possibility of hydrogen bond formation between the surface and the water molecules above it, which in turn makes it easier for the protein to move closer to the surface with hydroxyl modification. Introduction Protein adsorption onto surfaces of implants is of great interest in many fields, including biomaterials, biomedical devices, and biosensors, because of its primary importance for the subsequent cell adhesion, spreading, and proliferation, and for the regulation of biocompatibility and bioactivity of the implants. In particular, thanks to its lightweight and tensile strength, titanium has been extensively employed for medical implants such as dental implants, artificial joints, and blood-contacting devices. Titanium is generally regarded as a bioactive material with good biocompatibility, which mainly derives from the presence of the surface oxide film that protects the metal from further oxidation1 and from the induced formation of apatite layers which are believed as the main requirement for the bone-bonding ability of materials when in contact with simulated body fluids such as bone marrow, blood, and other tissues.2 So far, many proteins such as albumin,3 fibronectin,4 and laminin5 have experimentally been found to be able to adsorb onto titanium dioxide surfaces. It has become evident that the interactions among the proteins, the TiO2 surface, and the solvent, as well as the dynamic mechanism of the adsorption/desorption process are the key points to understand for the design of implants with optimal bioactivity. Molecular simulations can be seen as the most direct approach to elucidate the mechanism of protein adsorption on biomaterials. For example, lattice kinetic Monte Carlo simulations were used to investigate the surface-induced conformational changes of the adsorbed protein,6 and meanwhile molecular dynamics (MD) simulations were extensively performed to explore the atomic details taking place at the protein-adsorbent interface.7,8 In particular, much work has been devoted to the simulations * To whom correspondence should be addressed. E-mail: agren@ theochem.kth.se. † Royal Institute of Technology. ‡ Zhejiang University. § ¨ Orebro University.

of proteins/peptides, such as dipeptides,9 oligopeptides,10 and collagen fragments,11,12 adsorbed on the TiO2 surfaces. These studies have mainly focused on the interactions between the protein and the perfect TiO2 surface, and have indicated that the adsorption takes place via the side chains of the charged residues, in agreement with experimental findings. Through these studies the electrostatic interactions are confirmed to be responsible for the charged groups in proteins binding to the TiO2 surfaces. Most recently, the role of the interfacial layers of the water solvent has been advocated as crucial for the peptide initial recognition.13 The interfacial water on the TiO2 surface has thus been widely discussed, and both the molecular and dissociative water-surface interactions have been taken into account, with the latter mode found to be favored.14 It supports the notion that the protein adsorption process should be attributed to the interplay of many factors in the system. Required by the ever-increasing clinical needs for various implants, surface modifications of implants with peptides/ proteins,15,16 sol-gel ceramics,17 porous metals,18 and some functional groups19,20 have been proposed for improving the biologically specific surface properties. Since hydroxyl groups derived from the dissociative adsorption of water can affect the surface properties and consequently the initial adsorption of the protein on the surface, a comparison between the behavior of the nonhydroxylated and hydroxylated surfaces provides useful information to improve understanding of the protein adsorption on implants. Furthermore, the investigation on how surface modifications affect the protein adsorption process will help in the molecular design of biocompatible materials, biosensors, and bioactive implants, and in the control of surface properties against nonspecific adsorption of proteins.21 The objective of this work is to explore the difference between the protein adsorption behavior on the nonhydroxylated and hydroxylated rutile TiO2 (110) surface through MD simulations, and to elucidate the mediation of the interfacial water affected by the surface modifications. The human serum albumin, which

10.1021/jp1037156  2010 American Chemical Society Published on Web 08/10/2010

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Figure 1. Snapshots of initial configurations of rutile TiO2 (110) surfaces. (a) A unit cell of the hydroxylated surface. The Ti atoms are shown in green, O atoms in red, and H atoms in white. (b) Nonhydroxylated and hydroxylated surfaces set parallel to the x-y plane.

Figure 2. Snapshots of the six different starting arrangements of the protein-surface systems. The yellow line shows the top of the surfaces, namely the position of the bridging oxygen atoms in the nonhydroxylated surface, or that of the terminal hydrogen atoms in the hydroxylated surface. The color in the new cartoon model represents the secondary structure of the protein including R-helix (purple), 3-helix (blue), turns (cyan), and coils (white). The water molecules are not displayed here for clarity.

is the most abundant blood protein involved in the biocompatibility for biomaterials, was chosen as a model protein as it also has been extensively used for investigations of the protein adsorption process by both experiments and simulations.3,22,23 Simulation Details We have performed MD simulations of the protein human serum albumin (HSA) adsorbed onto two rutile TiO2 (110) surfaces: the nonhydroxylated surface and the fully hydroxylated surface with both bridging and terminal hydroxyl groups, as shown in Figure 1a according to the previous work,24 to investigate the effect of the modified hydroxyl groups on the surface properties. The surfaces modeled as five-layer titania slabs were set parallel to the x-y plane as shown in Figure 1b, and were frozen during the simulations, except that the bridging and terminal hydroxyl groups at the hydroxylated surfaces were kept flexible, with fixed Ti-O and O-H bond lengths and Ti-O-H angle. For briefness, hereafter the hydroxylated surface is denoted as the H surface, and the nonhydroxylated surface is called the N surface. The initial coordinates of the protein HSA were selected from the Protein Data Bank (PDB ID code 1AO6).25 This protein consists of three domains which are quite similar to one another in both topology and threedimensional structure and each domain can be divided into two

subdomains a and b. In this work, the subdomain IIIb (denoted as HSA_IIIb) made of 85 amino acids was derived as the model to adsorb onto the TiO2 surfaces. The secondary structure of HSA_IIIb is shown in Figure 2, using VMD.26 The colors in the new cartoon model represents R-helix (purple), 3-helix (blue), turns (cyan), and coils (white). In this study, all simulations were performed with the GROMACS program package.27,28 The AMBER03 all-atom force field29,30 was used for describing the protein and the TiO2 parameters were supplemented,24 in which the Lennard-Jones parameters of Ti and O atoms (see Table 1) were obtained from fitting to the Buckingham potentials. For the water molecule, the SPC/E water model31 was used. The cutoff for the nonbonded van der Waals interactions was set to 12 Å. The longrange van der Waals interactions are also taken into account by introducing the dispersion correction and neglecting the repulsion term, as implemented in the GROMACS program package,28 and the parameters of the Lennard-Jones potential for the cross interactions between nonbonded atoms were obtained from the Lorentz-Berthelot combination rule,32

εij ) √εiiεjj

(1)

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σij )

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(σii + σjj) 2

(2)

During the MD simulations, the Nose´-Hoover thermostat33,34 was employed to maintain a constant temperature at 310 K. Periodic boundary conditions were applied for all the simulations. The particle mesh Ewald (PME) summation35 was used to calculate the long-range electrostatic interactions, with a cutoff distance of 12 Å for the separation of the direct and reciprocal space. All the simulations were carried out in the canonical (NVT) ensemble with a time step of 2 fs, and with frames saved every 1 ps in the production runs. The protein was first immersed in the simulation box of water molecules and an MD simulation of 5 ns was performed to relax the structure, before it was placed close to the TiO2 surface, oriented with its longer axis parallel to the surface. Then six different starting arrangements were generated by rotating the protein in 60° around its longer axis, which are shown in Figure 2. Each system was immersed in a rectangular box of 64.969 × 53.244 × z Å3, where z is the box length along the direction perpendicular to the TiO2 surface. z varied from 64.780 to 66.660 Å to fit different starting orientations of the protein and was determined by making the shortest distances in the z-direction between the complex surface and the box wall larger than the cutoff distance. The box lengths in the x and y directions fit the crystal parameters of the surface, which creates infinite slabs in the x-y plane. In these systems, the number of water molecules contained varies from 5054 to 5068, according to the box sizes of the systems. Thereafter, a 5 ns MD simulation was performed for each system. The trajectory of the last nanosecond of each simulation was used for the analysis of interaction energy, which is defined as:

Eint ) Epro+surf - Epro - Esurf

(3)

where Eint stands for the interaction energy between HSA_IIIb and the surface and Epro+surf refers to the total energy of the protein combined with the surface. Epro and Esurf are energies of the protein and the TiO2 surface, respectively. The system with the strongest binding energy was chosen for further analysis. Hereafter, the data of all atom-surface vertical (in TABLE 1: Lennard-Jones Parameters and Atomic Chargesa of TiO2 Surfaces Used in This Work atom

σi (Å)

εi (kJ/mol)

qi (e)

Ti O protonated bridging O bridging H terminal hydroxyl O terminal hydroxyl H

1.9565 2.9273 3.1656 0.0000 3.1656 0.0000

2.5466 0.5866 0.6502 0.0000 0.6502 0.0000

2.196 -1.098 -1.035 0.486 -1.008 0.459

a All atomic charges are from ref 24. The Lennard-Jones parameters of Ti and O atoms are fitted from the Buckingham potentials in ref 24, and the Lennard-Jones parameters of -OH (bridging OH and terminal hydroxyl OH) are the same as those for the SPC/E water model in accordance with ref 24.

the z-direction) distance were calculated from a baseline of the surface layer of Ti atoms, which allows direct comparison with the positions of atoms on both surfaces. Results and Discussion 1. Protein-Surface Interaction. Figure 2 shows the initial configurations of HSA_IIIb on the two rutile (110) surfaces at the start of the MD simulations. The protein was initially placed close to the two surfaces separated by nearly the same distance from the surfaces. After a 5 ns simulation, the protein is observed adsorbed onto the surface for each system. The interaction energy between the protein and the surface in each system was calculated according to the trajectory of the last nanosecond in the production run; the system with the maximum interaction was then chosen for further analysis. Here we did not perform longer simulations for the surface-induced protein structural change, but focused on the different primary adsorption behavior affected by surface properties. While the chosen configuration may not be considered as the stable adsorption state in equilibrium, the mildly fluctuating root-mean-square deviation (rmsd) of the protein backbone (Figure S1 in the Supporting Information) implies that metastable states were achieved for the systems investigated. This time scale is considered to be adequate to investigate the difference of the protein adsorption affected by the surface properties. Table 2 shows the protein-surface interaction energy after the 5 ns simulations for the systems with the H or the N surface. The residues within 7 Å of the surface Ti atoms are considered as adsorbed residues and are listed in the table. The electrostatic interaction energy between the protein and the surfaces plays a dominant role in the protein adsorption onto both H and N surfaces. In both systems, the acidic and basic residues show great affinity to the surface, which means that -COO- and -NH3+ are the main adsorbed groups that interact with the surface. This phenomenon has been extensively reported in the previous simulations9-12 and experiments.36 Besides, the polar residue Thr69 and the nonpolar residue Ala72 are also found close to the surface owing to the van der Waals attraction. Clearly, the protein-surface van der Waals interaction in the two systems shows little difference, whereas the protein-surface electrostatic interaction in the H system is much larger than that in the N system; in the H system the charged residues take a larger proportion of the adsorbed residues. Thus, the TiO2 surface modified with -OH groups shows much greater affinity to HSA_IIIb owing to the greater protein-surface electrostatic interaction and more adsorbed residues. To confirm this we also apply an external force to all the backbone atoms of the protein to pull it away from the surface at a constant velocity in the z-direction, namely the direction perpendicular to the surface (Figure S2 in the Supporting Information). The stronger force applied on the system with the H surface means that protein desorption from the H surface is more difficult, which also indicates a stronger affinity of the H surface to the protein. 2. Adsorption Details at the Interface. Figure 3 shows the adsorption details on both surfaces. The interfacial water molecules are orientationally structured on both surfaces which form hydrogen bond networks induced by the surfaces; and the

TABLE 2: Protein-Surface Interaction Energy (kJ/mol) and the Adsorbed Residues (Within 7 Å of the Surface Ti Atoms)

a

surface

∆Eint

∆Eele

∆EvdW

adsorbed residuesa

hydroxylated nonhydroxylated

-947.50 -197.10

-841.78 -110.80

-107.74 -90.95

Lys3 Lys76 Lys77 Asp65 Glu73 Thr69 Ala72 Lys76 Asp65 Glu73 Thr69 Ala72

Acidic residues (red), basic residues (blue), polar residues (green), nonpolar residues (black).

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Figure 3. Snapshots of the adsorbed residues on (a) hydroxylated and (b) nonhydroxylated surfaces taken at 5 ns. The protein atoms within 7 Å of the surface Ti atoms are shown in the CPK model. Only the interfacial water molecules are shown for clarity; the hydrogen bonding networks among them are displayed as dashed white lines.

side chains of the residues adsorb onto the surfaces mediated by the interfacial water layers. Here we denote the first water layer on the N surface as L1 and the second water layer as L2; and correspondingly, the layer of terminal -OH groups on the H surface is denoted as L1 and the first water layer above the modified surface as L2. Clearly, more residues were adsorbed onto the H surface during the 5 ns simulations. As shown in Figure 3a, on the H surface, some groups, such as Asp65, Thr69, and Ala72 side chains, bind with water molecules in L2, and some groups, such as Glu73, Lys76, and Lys77 side chains, bind with the modified surface hydroxyl groups directly. This means that these protein groups replace the water molecules in the first layer (L2) above the H surface and form hydrogen bonds with the modified -OH groups on the surface. For example, the oxygen atoms in -COO- of Glu bind with the hydrogen atoms both in the terminal and in the bridging hydroxyl groups; and the hydrogen atoms in -NH3+ of Lys bind with the oxygen atoms in the terminal hydroxyl groups. In contrast, on the N surface, as shown in Figure 3b, the adsorbed groups do not

perturb the water molecules in L1 or L2, in agreement with the MD results of Skelton et al.13 The oxygen atoms in -COO- of Glu and Asp bind with the hydrogen atoms in water molecules in L1, while the hydrogen atoms in -NH3+ of Lys bind with the oxygen atoms in water molecules in L2. The vertical distances (in the direction perpendicular to the surface plane) between the adsorbed residues and surfaces are listed in Table 3 for comparison. Hereafter, all residue-surface or water-surface vertical separation data were calculated from the baseline of the surface layer of the Ti atoms. For Lys, Asp, Glu, and Ala groups, we measured the distances from the surface to the N atom in -NH3+, the carboxylate C atom, the carboxylate C atom, and the methyl C atom, respectively. For the Thr group, the adsorbed methyl H atom was chosen, which is the atom closest to the surface in the whole residue. The data in the last nanosecond of the trajectory were used for analysis. It can be seen from Table 3 that the residues Glu and Lys with charged groups are closer to the H surface. Especially on the H surface the Lys group reaches the region of L2 and binds with

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TABLE 3: Distances (nm) between the Adsorbed Residues and the Surfacesa residue

surface

min

max

mean

sd

Asp65

hydroxylated nonhydroxylated hydroxylated nonhydroxylated hydroxylated nonhydroxylated hydroxylated nonhydroxylated hydroxylated nonhydroxylated

0.566 0.467 0.390 0.474 0.334 0.490 0.581 0.448 0.626 0.564

1.075 1.320 0.418 0.714 0.400 1.142 0.807 0.729 0.819 0.833

0.728 0.695 0.448 0.527 0.482 0.714 0.672 0.575 0.708 0.673

0.102 0.234 0.008 0.040 0.024 0.148 0.037 0.060 0.031 0.046

Glu73 Lys76 Thr69 Ala72 a

Minimum (min), maximum (max), and average (mean) values as well as standard deviations (sd) are listed.

the terminal hydroxyl groups directly, something that seems to be difficult to take place on the N surface. Although Glu can bind with water molecules in L1 on the N surface, it does not replace the water in L2 as it does on the H surface. Here Asp is a little closer to the N surface because the carboxylate O atom binds to the water in L1 while on the H surface this residue chooses to bind the water in L2. This feature is probably because of the position of this residue in the direction parallel to the surface plane. During the adsorption, the protein undergoes a rational conformational change to maximize its affinity to the surface in order to decrease the free energy of the system. Thus not every residue in the protein can obtain its best binding configuration on the surfaces. In conclusion, on the N surface the acidic residues (in this case Glu) can get closer to the surface than the basic residues (in this case Lys) in agreement with the results from other simulations,13 while on the H surface the basic residues have the possibility to get closer to the surface, mainly due to the different distribution and orientation of the interfacial water layers. In addition, the standard deviations of the separation for all residues listed on the H surface are smaller than those on the N surface, which indicates that after the 5 ns simulation the protein on the H surface shows better stability than it does on the N surface. 3. Roles of Water Molecules at the Interfaces. To further explore the mechanism of the different behavior of the protein at the interfaces, more attention is paid to the water molecules at the interfaces. Here we first performed a 5 ns simulation for the system without the protein, namely the system of only the H surface and water molecules or that of only the N surface and water molecules, and calculated the average distributions of water oxygen in the last nanosecond of the trajectory in the direction perpendicular to the surface plane as well as the number of hydrogen bonds among water molecules which were considered as the data before the protein adsorption. Figure 4 shows the calculated distributions. The dashed line illustrates the distribution of the oxygen in the terminal hydroxyl groups. The vertical distributions of water oxygen atoms and the protein atoms after the adsorption are shown in Figure 5 for comparison. On both surfaces the interfacial water layers (L1, L2 on the N surface, and L2 on the H surface) are quite stable as reflected by the zero regions between the two peaks, in agreement with the work of Monti et al.6 Moreover, the separation of the two layers, or the gap between the two peaks on the H surface, is larger than that on the N surface. This observation means that the highly ordered structure of the modified terminal hydroxyl groups on the H surface may enhance the number of hydrogen bonds inside the layer and consequently reduce the possibility of H-bond formation between the atoms in this layer (L1) and those in the water layer (L2) next to it, which is similar to that

Figure 4. Vertical distributions of oxygen atoms on the surfaces as functions of the distance from the surface Ti atoms before the protein adsorption. OW denotes the oxygen atom in water and OH represents that in the terminal -OH groups.

Figure 5. Vertical distributions of (a) oxygen atoms in water (OW) and those in terminal -OH groups (OH) and (b) atoms of the protein after the adsorption, as functions of the distance from the surface Ti atoms.

found in the work of Wang et al.37 This in turn allows the protein to more easily move closer to the H surface as shown in Figure 5b. Here it is easy to find out that the protein can partially occupy the region of L2 on the H surface, but that it just reaches the region of the third water layer on the N surface. This conclusion is further proved by the statistics on the number of hydrogen bonds in the systems as shown in Table 4. In the 0.5 nm region above L1 (marked cyan in Figure 4), the numbers of H-bonds among water molecules on both surfaces are quite similar before the adsorption. After the adsorption, the water-water H-bonds apparently diminished in this region on the H surface, which indicates that some protein atoms occupy this region and reduce the probability of H-bond formation among the water molecules in the region. In contrast, on the N surface the water-water H-bonds in the region barely changed. It can also be found that before the adsorption, the H-bonds between the terminal hydroxyl groups and water molecules in L2 on the H surface are significantly smaller in

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TABLE 4: Changes in the Number of Hydrogen Bonds before and after the Protein Adsorption

surface

H-bonds in water molecules in cyan region marked in Figure 4 (before/after)

H-bonds between L2 and L1(before/after)

H-bonds bewteen protein and L1

H-bonds bewteen protein and L2

hydroxylated nonhydroxylated

232.73/220.27 233.95/234.96

166.99/188.05 191.06/190.22

6.97 3.14

11.27 5.71

number than the water-water H-bonds between L1 and L2 on the N surface. This means that on the H surface there are 166.99 H-bonds on average which link the two layers, while 191.06 H-bonds on average on the N surface, and that the larger number of interlayer H-bonds hinders the protein getting closer to the N surface. Interestingly, after the protein adsorption onto the H surface, the number of water H-bonds between L1 and L2 increased significantly. This indicates that with the protein adsorption onto the TiO2 surface, some water molecules around the protein move closer to the surface too, increasing the possibility of H-bond formation with the modified hydroxyl groups on the surface. This can also be reflected by the two L2 peaks on the H surface as shown in Figures 4 and 5a, which exhibit that after the adsorption the number density of water oxygen in L2 slightly increased although some protein atoms occupied the space in the region of L2. This may also explain that on the N surface the water-water H-bonds in the cyan region barely changed even though some protein atoms occupied this region. Here we conclude that the existence of the protein increased the probability of H-bond formation between water and the modified hydroxyl groups on the surface. In addition, the protein can get closer to the H surface as discussed above, resulting in the increase in the number of hydrogen bonds between the protein and the water molecules and/or modified hydroxyl groups as shown in Table 4, which is also energy favorable. Conclusion Molecular dynamics simulations have been performed to compare the mechanisms of protein HSA_IIIb adsorption onto two rutile (110) surfaces: the nonhydroxylated surface and the fully hydroxylated surface with bridging and terminal hydroxyl groups. On both surfaces the protein-surface electrostatic interaction is found to be the major factor for the protein adsorption. The surface modified with -OH groups shows much greater affinity to HSA_IIIb as reflected by the stronger protein-surface electrostatic interaction and larger number of adsorbed residues. Compared with those on the nonhydroxylated surface, the adsorbed groups with charges can get closer to the hydroxylated surface. Differently, on the nonhydroxylated surface the acidic residues such as Glu can get closer to the surface than the basic residues like Lys, while on the hydroxylated surface the basic residues may have the possibility to move closer to the surface, which is mainly attributed to the different distribution and orientation of the interfacial water layers, and referring to that the protein adsorbs onto the surface through binding with the structured water at the interface. On the hydroxylated surface, the highly ordered structure of the modified terminal hydroxyl groups may enhance the number of hydrogen bonds inside the layer and consequently reduce the possibility of H-bond formation between the modified hydroxyl groups and the interfacial water molecules. This in turn allows the protein to more easily move closer to the surface with the hydroxyl groups on which the side chains of the charged residues can replace the water molecules in the first layer above the modified hydroxyl groups and form hydrogen bonds with these groups. In contrast, on the nonhydroxylated surface the

residues hardly reach the region that perturbs the first or second water layers above the surface due to unfavorable energy consumption. Moreover, with the protein getting closer to the hydroxylated surface, the probability of hydrogen bond formation between the protein and interfacial water molecules and/ or modified hydroxyl groups effectively increases meanwhile some water molecules around the protein also move toward the interface owing to its hydrophilic surface, resulting in the increase of the H-bonds between the hydroxyl groups and the water molecules. From the brief outline above we find that the adsorption behavior of the protein on the surface, as strongly mediated by the interfacial water, can feasibly be manipulated via appropriate surface modification, which induces redistribution and reorientation of the water molecules at the interface. These findings may be of help in the molecular design of biocompatible materials, biosensors, and bioactive implants for specific adsorption of proteins. Acknowledgment. This work was supported by a grant from the Swedish Infrastructure Committee (SNIC) for the project “Multiphysics Modeling of Molecular Materials”, SNIC 022/ 09-25. Supporting Information Available: Figures showing the root-mean-square deviation (rmsd) of the protein backbone on hydroxylated and nonhydroxylated surfaces during the simulations and steered molecular dynamics simulations performed in both systems. This material is available free of charge via the Internet at http://pubs.acs.org. References and Notes (1) Liu, X.; Chu, P. K.; Ding, C. Mater. Sci. Eng., R 2004, 47, 49– 121. (2) Serro, A. P.; Fernandes, A. C.; Saramago, B.; Lima, J.; Barbosa, M. A. Biomaterials 1997, 18, 963–968. (3) Sousa, S. R.; Moradas-Ferreira, P.; Saramago, B.; Viseu Melo, L.; Barbosa, M. A. Langmuir 2004, 20, 9745–9754. (4) Strehle, M. A.; Ro¨sch, P.; Petry, R.; Hauck, A.; Thull, R.; Kiefer, W.; Popp, J. Phys. Chem. Chem. Phys. 2004, 6, 5232–5236. (5) Tamura, R. N.; Oda, D.; Quaranta, V.; Plopper, G.; Lambert, R.; Glaser, S.; Jones, J. C. R. J. Periodontal Res. 1997, 32, 287–294. (6) Zhdanov, V. P.; Rechendorff, K.; Hovgaard, M. B.; Besenbacher, F. J. Phys. Chem. B 2008, 112, 7267–7272. (7) Ganazzoli, F.; Raffaini, G. Phys. Chem. Chem. Phys. 2005, 7, 3651– 3663. (8) Cole, D. J.; Payne, M. C.; Ciacchi, L. C. Phys. Chem. Chem. Phys. 2009, 11, 11395–11399. (9) Monti, S.; Carravetta, V.; Zhang, W.; Yang, J. J. Phys. Chem. C 2007, 111, 7765–7771. (10) Carravetta, V.; Monti, S. J. Phys. Chem. B 2006, 110, 6160–6169. (11) Ko¨ppen, S.; Ohler, B.; Langel, W. Z. Phys. Chem. 2007, 221, 3– 20. (12) Monti, S. J. Phys. Chem. C 2007, 111, 6086–6094. (13) Skelton, A. A.; Liang, T.; Walsh, T. R. ACS Appl. Mater. Interfaces 2009, 1, 1482–1491. (14) Scaranto, J.; Giorgianni, S. Mol. Phys. 2008, 106, 2425–2430. (15) Ferris, D. M.; Moodie, G. D.; Dimond, P. M.; Giorani, C. W. D.; Ehrlich, M. G.; Valentini, R. F. Biomaterials 1999, 20, 2323–2331. (16) Kinnari, T. J.; Peltonen, L. I.; Kuusela, P.; Kivilahti, J.; Ko¨no¨nen, M.; Jero, J. Otol. Neurotol. 2005, 26, 380–384. (17) Piveteau, L. D.; Moner, I.; Girona, M.; Schlapbach, L.; Barboux, P.; Boilot, J. P.; Gasser, B. J. Mater. Sci.: Mater. Med. 1999, 10, 161–167.

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