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Simulation of the adsorption mechanism of titanium-binding peptide to TiO 2 anatase surface

Lorenzo Agosta1, Caterina Arcangeli2,3∗, Francesco Buonocore2,3,

Massimo Celino2,3, Fabrizio Gala1, Giuseppe Zollo1

1Department of Fundamental and Applied Sciences for Engineering

University of Rome ”La Sapienza” Via A. Scarpa 14-16, I-00161 Rome, Italy

2NAST Centre c/o University of ”Tor Vergata”, Department of Physics

Via della Ricerca Scientifica, 1, I-00133 Rome, Italy

3ENEA, Italian National Agency for New Technologies,

Energy and Sustainable Economic Development C. R. Casaccia, Via Anguillarese 301, I-00123 Rome, Italy

Abstract. Organic-inorganic interfaces are nowadays playing a major role in several technological fields ranging from photovoltaics to drug-delivery, from microelectronics to composites. However they are very challenging from the experimental point of view because the microscopic features giving raise to their exceptional properties involve very small distances and very small energies. For this reason the modelling approach can act as a powerful microscope to see and measure the relevant physical and chemical quantities. A model for amino acids adhesion on a widely used inorganic surface has been developed and implemented on the high performance computing platform CRESCO.

Abbreviations: MD: Molecular dynamics; DFT: Density Functional Theory; Ala: Alanine; Cys: Cysteine; Arg: Arginine; Lys: Lysine; Asp: Aspartic acid.

1

Introduction

Interfaces between biological matter and inorganic materials are now among one of the hottest research topics in various research fields and even in industry. Recent progress in combinatorial biology (e.g. the phage display method) has permitted to select amino acid sequences possessing specific affinities to their target inorganic materials. Among peptide sequences that bind inorganic surfaces the sequence AMRKLPDAPGMHC has been demonstrated to display a large and selective affinity to titanium dioxide [1]. Ex- perimental characterization of the peptide-titania interface has revealed that electrostatic

interactions play a role and that peptide flexibility may also be important [2, 3]. The un- derstanding of these interfaces paves the way to the design of novel materials engineered at the nanometric scale. In order to shed some light on this interaction, we investigated at atomic level the binding mechanisms between the TiO2 anatase surface and the peptide.

2

Computational details

The simulation of the peptide-titania interface consisted of three stages: 1) the modeling of the peptide folding through classical MD simulations in water, starting from a totally unfolded molecular conformation. 2) DFT calculations to characterize the hydrated inor- ganic surface and the adhesion of the amino acids (relevant to the binding) on the TiO2 anatase in the presence of water molecules. 3) MD simulations of the folded peptide adsorbed onto the TiO2 surface in water solution and steered MD simulations to better investigate the force of the interaction between the peptide and the TiO2 surface. The DFT calculations and MD simulations were carried on CRESCO HPC cluster by using the Quantum Espresso code and the highly optimized parallel version of GROMACS (version 4.5.4), respectively.

3

Results and Discussions

3.1 Modeling the peptide folding by MD simulation

MD simulation of the folding of the peptide in water were performed starting from a totally unfolded conformation. Most of the residues of the peptide assumes a bended conformation that is maintained stable during the last 5 ns of simulation (Fig. 1). An intra-molecular hydrogen bond between the N atom of the Ala1 and the O atom of the terminal carboxyl group of Cys13 stabilizes the bended peptide [4].

3.2 DFT calculations

The TiO2 (101) anatase surface was reconstructed with adsorbed water molecules (Fig. 2). The adsorption energy of water molecules was calculated as -0.729 eV/molecule. Therefore it is expected that in water solution, water molecules mediate the peptide adsorption. As a first step towards the understanding of the peptide adhesion, we considered the adsorption properties of the three isolated amino acids as if they were charged according to their charge states in neutral water solution. The water molecules completely mediate the adhesion process [5] (Fig. 2). DFT calculations show that the three amino acids have negative adsorption energy (i.e. stay stacked on the surface spontaneously). However Lys and Arg are largely more stable than the Asp. While on the dry surface Lys and Arg have nearly the same adsorption energy [5] on the hydrated surface Arg is more stable than Lys by nearly 220 meV (Table 1). Then it is likely that the main responsible of the peptide adhesion is Arg even though this conclusion is drawn without taking into account the peptide structure that might play a significant role.

Figure 1: Snapshots of the peptide at selected time points of the MD simula- tion. The peptide backbone is shown as a cyan tube while the Arg3 and Asp7 are represented through CPK model. The movie of the folding simulation is at https://www.afs.enea.it/project/cmast/index.php.

Figure 2: Relaxed configuration for two water molecules on (101) anatase surface and adsorption of amino acids relevant for the adhesion on the hydrated TiO2 surface.

3.3 MD simulation of the peptide-TiO2 interface

The folded peptide was placed close to the TiO2 surface (d=1.0 nm)[4]. The configuration of the adsorbed folded peptide onto the surface after 5 ns of MD simulation (Fig. 3 left) shows that the interfacial water molecules are stable and oriented on the surface to form a hydrogen bonding network induced by the surface (white dashed lines). The side-chains of Asp7 and Arg3 adsorb on the surface mediated by the interfacial water layer. The effect of the adsorbed peptide on the structure of the interfacial water was investigated. The plane

Arg Lys Asp Dry(101) -2.297 -2.362 -1.277 Hydrated (101) -1.703 -1.923 -0.427

Table 1: Adsorption energies (eV) of amino acids on the (101) anatase surface with and without water.

containing the surface ranges from 1.9 to 2.5 nm and defines two interfaces. The left water- surface is free from the peptide; the right water-surface is affected from the presence of the peptide. The density profiles for both exposed surfaces show distinct peaks corresponding to different hydration layers (Fig. 3 right). The presence of the peptide causes a decrease of the local water density. The atoms of the Arg3 and Asp7 are in the 1st and 2nd adsorbed water layer (Fig. 3 right b). To better investigate the force of the interaction between the peptide and the surface, the peptide was detached from the surface along the z-direction by pulling on the COM using k= 5000 kJ/mol/nm2 and a pull rate of 0.0005 nm/ps.

Figure 3: Left: Snapshots of side view (left) of the adsorbed peptide onto TiO2 (101) anatase surface taken at 5 ns. Right: Density profile as a function of z-axis for water (a) and peptide atoms (b).

The pulling force builds up until three breaking points are reached, at which the interac- tions between the Cys13, Asp7 and Arg3 with the metal surface are disrupted, allowing the peptide to dissociate from the metal surface (Fig. 4). A similar behaviour has been ob- served for desorption of the hexapeptide RKLPDA from a natively oxidized TiO2 surface [6]. The dissociation pathway is shown in Fig. 5.

Figure 4: Pulling force applied as a function of simulation time.

Figure 5: Snapshots of the dissociation pathway (from the top left to the bottom right) of the peptide from the TIO2 surface.

4

Conclusions

Atomic scale modelling is able to provide interesting insights in the design of novel materi- als. In the case of biomolecules interacting with inorganic surfaces, modelling can compute the adhesion properties and how these influence the physical and chemical properties. By means of accurate and extensive DFT simulations, we confirm the major role of the elec- trostatic interactions to the binding mechanism. Classical MD simulations of the interface enlighten that the adhesion mechanism is mediated by the interfacial waters. The dissoci- ation pathway, obtained by steered MD simulations, suggests an anchoring of the peptide

to the surface via Cys13 Asp7 and Arg3 residues. Our results may have important impli- cations for nanotechnology and material science applications offering a rational design of material-selective peptides.

Acknowledgements

This work was supported by META-Materials Enhancement for Technological Application- Project (FP7-PEOPLE-2010-IRSES-Marie Curie Actions, PIRSES-GA-2010-269182). We acknowledge the technical support of the ENEA-ICT team who provided the access to the ENEA-CRESCO high-performance computing facility (www.cresco.enea.it). We thank Dr. S. Giusepponi for helpful discussions and suggestions.

References

[1] Sano KI. and Shiba K. A hexapeptide motif that electrostatically binds to the surface of titanium. J Am Chem Soc, 125:14234–5, 2003.

[2] Hayashi T et al. Mechanism underlying specificity of proteins targeting inorganic materials. Nano Letters, 6:515–9, 2006.

[3] Fukuta M. et al. The adsorption mechanism of titanium-binding ferritin to amphoteric oxide. Colloids Surface, B(102):435–40, 2013.

[4] Arcangeli C. et al. Organic functionalization of metal oxide surfaces: An atomic scale modeling approach. Nanosci Nanotech Lett, 5:1147–54, 2013.

[5] Agosta L. et al. Submitted to Physical Chemistry Chemical Physics 2014.

[6] Schneider J. et al. Specific material recognition by small peptides mediated by the interfacial solvent structure. J Am Chem Soc, 134:2407–13, 2012.

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