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Applied Surface Science

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Full Length Article

Underwater adhesion of mussel foot protein on a graphite surface

Mengdi Zhao, Liyi Bai, Joonkyung Jang⁎

Department of Nanoenergy Engineering, Pusan National University, Busan 46241, Republic of Korea

A R T I C L E I N F O

Keywords:Mussel foot proteinL-3,4-dihydroxyphenylalanineGraphiteWet adhesion

A B S T R A C T

Mussel foot proteins (MFPs) strongly adhere to virtually any surfaces under wet conditions. This remarkableadhesion of MFP onto a hydrophilic surface could be attributed to the hydrogen bonds formed between MFP andsurface. Little is known about the molecular origin of the underwater adhesion of MFP onto a nonpolar hy-drophobic surface. By using all-atom molecular dynamics simulation, we investigate the structure, dynamics,and energy of the wet adhesion of a MFP onto a hydrophobic graphite. The MFP anchors on the graphite bydirectly contacting three L-3,4-dihydroxyphenylalanine (DOPA) groups. The present adhesion of MFP is evenstronger than for a hydrophilic surface and arises from the van der Waals (π -π stacking) interaction between thephenylene rings of DOPAs and graphite.

1. Introduction

Marine mussels strongly and irreversibly adhere to practically any(hydrophilic or hydrophobic) surface in water. This remarkable water-resistant adhesion of mussel is strong, universal, and by far superior tothat of any synthetic adhesive. As mussels are biologically and en-vironmentally friendly as well, developing such an adhesive opens updiverse applications, for example, for cell encapsulants [1] and biolo-gical binders [2] such as bone sealing [3] and coronary artery coatings[4].

A marine mussel anchors on a surface through its threads whichform plaques on the surface (Fig. 1). Various mussel foot proteins (MFPs)are found in the plaques, as depicted Fig. 1. Especially, MFPs 3 and 5are known to be mainly responsible for the mussel adhesion. Notice-ably, all these MFPs have high percentages of L-3,4-dihydrox-yphenylalanine (DOPA), a post-translational modification of tyrosine.MFPs 3 and 5 have 21 and 28% of DOPA in their amino acid sequences[5].

Rational design of a biomimetic adhesive similar to MFP is ham-pered by the lack of understanding of the molecular mechanism un-derlying the wet adhesion. Previously, the adhesion of a MFP onto ahydrophilic silica has been studied both theoretically and experimen-tally [6–8]. In that case, the adhesion of MFP originates from themultiple hydrogen bonds formed between the MFP and the hydroxylgroups of the surface. Currently however, the adhesion of MFP on anonpolar hydrophobic surface is poorly understood, especially at themolecular level.

An experimental revelation of the molecular details of the adhesion

of MFP seems challenging however, considering the complexity of theprotein and its interaction with a surface. Therefore, we use all-atommolecular dynamics (MD) simulation to uncover the structure, dy-namics, energetics for the underwater adhesion of a MFP on a hydro-phobic surface. Specifically, we study the adhesion of MFP-3 onto agraphite surface. The molecular dynamics of the adhesion of MFP-3 isstudied by focusing on the role of DOPAs in the adhesion. By examiningthe geometry of the adsorbed MFP-3, we uncover the origin of theunderwater adhesion. We estimate the strength of adhesion by con-structing the free energy profile of the adhesion. We find the DOPAsindeed play a central role in the adhesion by directly contacting thegraphite with their phenylene rings parallel to the surface. The adhe-sion originates from the van der Waals (π-π) interaction between theprotein and surface and stronger than that found for a hydrophilic silicasurface.

2. Simulation methods

The AMBER [9] and TIP3P force fields are, respectively, employedto model the MFP-3 and water molecules. The long-ranged electrostaticinteraction is handled by using the particle-mesh Ewald method. Thevan der Waals interactions between atoms are cut off at a distance of1.2 nm [10]. All the MD simulations are carried out in the NVT en-semble with temperature fixed to 300 K. Temperature is kept constantby using the V-rescale thermostat method with a relaxation time of0.1 ps [11]. We use the LINCS [12] and SETTLE [13] algorithms, re-spectively, to constrain all the bonds involving hydrogen atoms withinthe MFP-3 and the internal geometry of a water molecule. The leap-frog

https://doi.org/10.1016/j.apsusc.2020.145589Received 29 September 2019; Received in revised form 20 December 2019; Accepted 29 January 2020

⁎ Corresponding author.E-mail address: jkjang@pusan.ac.kr (J. Jang).

Applied Surface Science 511 (2020) 145589

Available online 30 January 20200169-4332/ © 2020 Elsevier B.V. All rights reserved.

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algorithm with a time step of 1 fs is used to propagate the MD trajec-tory.

To obtain the structure of the MFP-3 folded in water, we firstroughly predict the structure from the primary sequence of MFP-3(ADYYGPNYGPPRRYGGGNYNRYNRYGRRYGGYKGWN NGWNRGRRG-KYW) [14] by using the Rosetta ab initio modeling [15–16]. The Rosettamodeling searches the homologues of a protein in the structure data-base and then assemble fragments using the empirical intermolecularforce fields [17]. After this, we change each tyrosine of the primarysequence to DOPA. The MFP-3 with a net charge of + 10 e is neu-tralized in a 0.15 M NaCl solution by adding 10 chloride ions, toemulate a typical experimental condition. Then, by using the Amberforce field modified for DOPA [18], we run all-atom MD simulation for210 ns to generate 2100 structures of MFP-3. The backbones of thesestructures are grouped into several conformers by applying the clus-tering algorithm of Daura et al. [19] Two conformations of MFP-3 aretaken to be the same if the root-mean square distance (RMSD) of theirbackbone structures are less than 0.4 nm. Fig. 2 illustrates the struc-tures of four dominant conformers of MFP-3, along with their relativepopulations. We study the underwater adhesion for the top two rankedconformers (conformers 1 and 2).

The graphite surface consists of three graphene sheets separatedfrom each other by 3.395 Å. The CeC bond length of graphene is takento be 1.42 Å to match that reported in an experiment [20]. We treat thegraphite as uncharged sheets of immovable sp2-hybridized carbonatoms implemented in the Amber force field. The carbon atoms interactwith the atoms of MFP-3 via the Lennard-Jones potential [21]. TheMFP-3 is placed in a simulation box with a dimension of7.67 × 7.87 × 7.20 nm3. The periodic boundary conditions are appliedalong the all three directions. The center of mass (COM) of MFP-3 isdefined as the average position of all the atoms (total of 801 atoms) ofMFP-3 weighted by atomic masses. The COM of MFP-3 is initiallyplaced at 9.5 Å above the top layer of graphite, together with the sur-rounding water molecules. We first minimize the energy of the system

by relaxing water molecules with the steepest descent method. We thenrun a 100 ps MD simulation to equilibrate the water molecules withrestraining the backbone atoms of the protein. Finally, we run 25 nsproduction simulations without any restraints by using a 1 fs time step.All the figures are created by using PyMol [22] and Visual MolecularDynamics [23].

We calculate the potential of mean force (PMF) vs. the height of MFP-3, H. The height is defined by the height of the COM of MFP-3 from thetop layer of the graphite. We use the umbrella sampling [24] to vary Hfrom 15 to 45 Å and from 12 to 43 Å for conformers 1 and 2, respec-tively (with an increment of 0.15 Å). For each H in the PMF curve, atotal of 5 ns simulation is run by imposing the harmonic force with aforce constant of 8000 kJ mol−1 nm−2 to constrain H to a specificvalue. The PMF profile is obtained by employing the weighted histo-gram analysis method [24]. The umbrella sampling MD simulation iscarried out by using the same methods used in the normal MD simu-lation above. All the MD methods above are implemented by usingGromacs 5.1.4 software [25].

3. Results and discussion

We examine the structure of the MFP-3 folded in water. The foldingstructures of MFP-3 can be grouped into four dominant conformationsshown in Fig. 2. Each conformer has an α helix without any β-sheet andis mainly disordered with turns and coils. This is consistent with the factthat the crystalline structure of MFP-3 is not found experimentally [26].The present structures of MFP-3 differ from those simulated by Qinet al. [6] which have beta sheets. This discrepancy might arise from thedifference in the force fields used to describe DOPA: we use the forcefield previously derived from the AMBER [18], while Qin et al. developthe force field for DOPA on their own based on the CHARMM force field[27]. Both the AMBER and CHARMM force fields are widely used insimulating proteins, because they reproduce the experimental struc-tures of proteins with a reasonable accuracy [28–30]. There are few

Fig. 1. Schematics for various mussel foot proteins (MFPs) found in the plaques of a mussel adhered on a surface. At least six types of MFPs (1–6) are found and theseare shown according to their relative heights in the plaque.

Fig. 2. Four major conformers of MFP-3 pre-dicted from the present all-atom MD simulation.The proteins are represented in a Newcartoonstyle. 2100 structures of MFP-3 are grouped intofour main conformations by using a clusteringalgorithm which checks the similarities of thebackbone structures. If the root-mean-squaredistance (RMSD) between two backbone struc-tures are within 0.4 nm, two structures are takento be in the same conformation.

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studies which discuss the advantages and disadvantages of these forcefields in specific contexts. For example, the simulation by Robertsonet al. shows the secondary motif of a protein-ligand complex is bettercaptured by the AMBER (ff14SB) than by CHARMM [31]. On the otherhand, the AMBER force field tends to make a high ratio of α-helices[32], although the recent AMBER (ff14SB) force field is corrected tosuppress the over-expression of the helicity [33]. In calculating theultraviolet adsorption spectra of proteins, the CHARMM point chargesoverestimate the experimental excitation energies, compared to theAMBER charges [34]. Overall, the CHARMM and AMBER force fieldsagree with each other in modeling the folding of a protein, only dif-fering in the minor details such as the residual structures[35,36].

We visually inspect the time progression of the underwater adhesionfor conformers 1 and 2. Representative snapshots of conformers 1 and 2at different times are shown in Fig. 3a and b respectively. Both con-formers (whose COMs are initially 25.7 and 23.2 Å above the surface)spontaneously adhere to the surface within 25 ns. Conformer 1 adhereby directly contacting 8 amino acids: three DOPAs (Y8, Y29, and Y32),two arginines (R27 and R28), two glycines (G30 and G31), one lysine(K33). Conformer 2 has 11 amino acids contacting the surface: threeDOPAs (Y8, Y25, and Y29), three asparagines (N7, N36, and N37), twotryptophans (W35 and W48), one arginine (R28), one lysine (K33), andone glycine (G34). For both conformers, three DOPAs directly contactthe graphite. Especially, Y8 and Y29 are involved in the adhesion of theboth conformers.

In Fig. 4, we examine in more detail the geometries of three DOPAsin contact with the graphite. For both conformers, the phenylene ring of

Y8 is nearly parallel to the surface and in contact with the graphitewithout intervening water molecules. This implies that the adhesion ofY8 arises from the π-π stacking interaction between the DOPA andgraphite. The other two DOAPs of conformer 1 (Y32 and Y29) areslightly tilted by about 30° and 5° from the parallel orientation of thephenylene ring. Nevertheless, there are no water molecules interferingand hampering the contact of these DOPAs with the graphite. TwoDOPAs of conformer 2, Y25 and Y29, are nearly parallel in orientationwithout intervening water molecules below them (Fig. 4b). The presentparallel or lying-down orientation of the phenylene ring of DOPAcontrasts with the vertical or standing-up orientation found for theadhesion of DOPA on a hydroxylated silica surface [7]. Note, amongthree DOPAs contacting the graphite, only Y8 sticks out of the mainbody of MFP-3 while other two DOPAs are wrapped inside the body ofthe protein, for both conformers. Given the parallel orientation is idealfor π-π stacking, Y8 is flexible in its orientation because it is outside themain body of MFP-3 and therefore takes the parallel orientation. Thetwo DOPAs inside the main body of MFP-3 however have structuralstrains that prevent the complete freedom to take the parallel orienta-tion. For conformers 1 and 2 are different in structure, the structuralstrain on Y29 will be different for conformers 1 and 2. Therefore, theorientation of the phenylene ring of Y29 is different for conformers 1and 2. If we repeat the simulation of the adhesion of MFP-3 using dif-ferent initial conditions, the overall structure of the adhered MFP willbe the same, but the orientation of Y29 might be slightly different, dueto the inherent thermal fluctuations of the protein structure and waterenvironment. More detailed views on the time-dependent orientations

Fig. 3. Time progression of the underwater adhesion of MFP-3 on a graphite surface. Representative snapshots of MD simulation are shown for conformers 1 (a) and 2(b). The MFP-3 is shown in the Newcartoon style and the adsorbed DOPAs in the bond style. Water molecules and counter ions are not shown for visual clarity of theprotein. Only the top layer of graphite is drawn.

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of three DOPAs contacting the graphite are available in the SupportingInformation (Fig. S1). The previous computational studies also reportthat the π-π stacking interaction is the main interaction between thearomatic residues of protein and carbon-based nanomaterials [37,38].Our finding also agrees with the previous experimental report thatDOPA takes the parallel and perpendicular orientations on hydrophobicand hydrophilic surfaces, respectively [39].

At the atomic scale, a hydrophilic surface is characterized by theatomic charges or polar chemical groups capable of forming hydrogenbonds with water molecules. A hydrophobic surface, by contrast, isnonpolar and interacting with water molecules only through the weakdispersion (van der Waals) interaction. DOPA has a Janus-like propertyin that it has both the polar hydroxyl groups and the nonpolar aromaticring which, respectively, can interact with a surface through hydrogenbonds and dispersion interactions. This is presumably the origin of theuniversal adhesive ability of MFP-3 on both hydrophilic and hydro-phobic surfaces.

We quantitatively study the dynamics of adhesion by following theheight of MFP-3 from the graphite, H (Fig. 5a and b). The inset of Fig. 5shows the heights of the COMs of three DOPA residues measured fromthe top layer of graphite. Here, the COM of each DOPA residue is ob-tained by averaging (weighted by atomic masses) over the positions ofall the 22 atoms belonging to DOPA. The height of the COM of MFP-3decreases from 25.7 and 23.2 Å and levels off to 13 and 10 Å forconformers 1 and 2, respectively, within 10 ns. For conformer 1, Y29 isthe quickest in the surface anchoring within 4 ns and then Y8 adsorbsaround 5.9 ns. Y32 finally adheres at around 15 ns. For conformer 2, Y8adheres at around 0.68 ns followed by Y29 which adheres at around0.86 ns. Y25 on the other hand adheres around 25 ns. Although notshown in the figure, we check the RMSD of the backbone structure ofeach conformer from its initial structure (translation of conformer as awhole is excluded in the calculation of RMSD). The RMSD settles downafter 10 ns, signifying the structure of protein is stabilized after adhe-sion to the graphite.

The Waite group [40] reports the lysines might play some role in theadhesion of MFPs. It is unclear however exactly how lysines contributeto the adhesion of MFP. We follow the dynamics of two lysine groups ofconformer 1. Indeed, one of the lysines, K33, co-adsorbs with the DOPA

Fig. 4. Geometries of three DOPAs adsorbed onto the graphite surface in water. Three DOPAs in contact with the graphite surface are shown for conformers 1 (a) and2 (b). In each panel, top and side views of DOPAs are shown. Water molecules and the rest of amino acids of MFP-3 are not shown for visual clarity.

Fig. 5. Dynamics of the underwater adhesion of MFP-3. Time variation in theheight of the COM of MFP-3, H, are drawn for conformers 1 (a) and 2 (b).Shown as insets are the time-dependent Hs of the COMs of three DOPAs an-chored on the surface.

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next to it (Y32). Fig. 6 illustrates the dynamics of the adhesion of K33along with Y32. We find K33 first adsorbs at around 3.3 ns and laterY32 adheres at around 15 ns. Before K33 anchors on the surface (a), thegraphite is covered almost entirely by water molecules. Once K33 an-chors on the graphite at 4.5 ns (b), a substantial portion of the surface isdepleted with water. The water-depleted area on the surface furtherexpands with the surface anchoring of Y32 at 15 ns. We thereforeconclude the lysine serves as a precursor of the wet adhesion of theneighboring DOPA.

We estimate the strength of adhesion of MFP-3 by calculating thefree energy profile in the detachment of the MFP-3 initially anchored onthe graphite. The free energy profile is obtained by calculating thepotential of mean force (PMF) vs. H. As shown in Fig. 7, the PMF in-creases by increasing H from the minimum located at H = 1.6 and1.3 nm for conformers 1 and 2, respectively. With increasing H to 3.5and 3.7 nm for conformers 1 and 2, respectively, the PMF reaches theplateau. Therefore, the attraction between the MFP-3 and graphite isranged over distances of 1.9 and 2.4 nm for conformers 1 and 2 re-spectively. This range is certainly longer than the typical range of thevan der Waals interaction between molecules (~1 nm). The adhesionenergy of MFP-3 is defined as the difference between the maximum andminimum of the PMF curve. This way, the adhesion energies of con-formers 1 and 2 are 55 kcal/mol and 65 kcal/mol, respectively. Qinet al. [6] report an adhesion energy of 18.1 kcal/mol for the MFP-3adhered on a hydroxylated silica. It seems difficult to compare theseadhesion energies quantitatively, because different force fields (AMBERvs. CHARMM) are used in the present work and the calculation by Qin

et al., let alone the fact that the surfaces are different. The insets ofFig. 7 illustrate that the secondary structure of MFP-3 is destroyed asthe protein is pulled away from the graphite. As the secondary structureof protein is maintained via hydrogen bonds, we check the number ofthe hydrogen bonds within MFP-3. This number decreases in the courseof the pull-off process, signifying the gradual destruction of the sec-ondary structure of MFP-3. Therefore, the adhesion is stronger than thecohesion of the secondary structure held by the hydrogen bonds.

We calculate the adhesion energy per area which is commonly re-ported in simulation studies [41]. The contact area (CA) between theprotein and surface is calculated as CA = (SA-Sprotein + SASsurface − SAScomplex)/2, where SASprotein, SASsurface, andSAScomplex are the solvent accessible surface (SAS) areas of the isolatedMFP-3, of the pristine graphite surface, and of the protein-surfacecomplex, respectively. With time, CA converges to 9 and 10 nm2 forconformers 1 and 2, respectively. The adhesion energies per areatherefore are given by 13.5 and 13.1 mJ/m2 for conformers 1 and 2,respectively. These adhesion energies per area are somewhat largerthan those obtained experimentally [39] for the MFP-3 adhered on ahydrophobic organic film, 7.7 mJ/m2. Besides the fact that the ex-periment uses a surface more flexible than ours, we note that the ex-periment employs a surface force apparatus in which MFP-3 is attachedto two identical and opposing surfaces. With such an experimentalsetup, the MFP will snap at a lower strength than in the present si-mulation setup where MFP-3 interacts with a single graphite surface.This is presumably why the experimental adhesion energy is lower thanthat of our simulation.

Fig. 6. Time-dependent heights Hs of the COMs of the DOPA, Y32, and the lysine, K33, of conformer 1. Three snapshots taken at 2.8, 4.5, and 15.3 ns are shown in(a), (b), and (c), respectively. Also shown are water molecules within a height< 6.5 Å above the surface. Drawn in the inset is the side view of Y32 and K33 adsorbedon the surface.

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Obviously, MFP-3 must displace water molecules pre-adsorbed onthe graphite in order to anchor on the bare graphite. It is well knownthat the water adsorbed on a surface differs from the bulk water instructure [42–45]. We find the water on the graphite is ordered in itsmolecular packing up to the second hydration layer from the surface(Fig. 8a): the density profile along the height from the surface Z showsthe distinct first and second peaks located at 0.35 and 0.6 nm, resepc-tively. This indicates that the interfacial water is ordered in the packingalong the surface normal upto two hydration layers. We investigate howthe hydration layers change with progression of the adhesion of MFP-3.Fig. 8 illustrate time-dependent snapshots of water molecules withheights Z < 6.5 Å (up to the second layer from the surface). With time,a water-depleted area on the graphite develops, widens, and coverges to9 and 10 nm2 for conformers 1 and 2, respectively (see above). It can bealso seen that the depleted area laterally moves before the completeadhesion of MFP-3. The depletion of water near the contact area ofMFP-3 and graphtie can be thought of as a drying transition of water dueto the confinement between two hydrophobic objects [46]. The re-sulting force due to the drying transition, called the hydrohobic force, isknown to be longer ranged and greater than the force due to the

Fig. 7. Free energy profile for the underwater adhesion of the MFP-3 onto agraphite surface. The PMF vs. the height of the COM of MFP-3 from the gra-phite, H, is drawn for conformers 1 (a) and 2 (b). Representative snapshots aredrawn for four different Hs marked as symbols in the PMF curve of each panel.

Fig. 8. Density profile of water taken along the height from the graphite surfaceZ (a). The densities ρs are calculated for the case where the protein does notexist. Time variations of the hydration layers formed on the graphite in theadhesion of MFP-3 (b and c). Time-dependent snapshots of water moleculeswith their Z coordinates< 6.5 Å are shown for conformers 1 (b) and 2 (c).

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hydrogen bond formation or the van der Waals interaction [47,48].Presumably, this is why the adhesion strength of MFP-3 on the graphiteis larger and logner ranged than found for the adhesion on a hydro-philic surface.

4. Conclusions

The efforts to develop a water-resistant adhesive mimicking theMFPs are hampered by incomplete understanding of the molecularmechanism underlying the remarkable underwater adhesion of MFP.Especially, the adhesion of MFP on a nonpolar hydrophobic surface ispoorly understood. We focus on the wet adhesion of MFP-3 onto agraphite surface. Given the experimental difficulties in unravelling themolecular details, we opt for all-atom molecular dynamics simulation.The MFP-3 adheres to the graphite even more strongly than to a hy-drophilic surface, mainly through three DOPAs contacting with thegraphite. These DOPAs displace the pre-adsorbed water and have theirphenylene rings parallel to the surface. The driving force for the ad-hesion is therefore the van der Waals or π-π interactions, in contrast tothe hydrogen bonds found for the adhesion of MFP-3 onto a hydro-xylated silica. The displacement of pre-adsorbed water and subsequentcontact of three DOPAs resemble the drying transition of the water pre-adsorbed on the graphite. Consequently, the adhesion on the graphite isranged over a longer distance and stronger than onto a hydrophilicsurface. The present molecular details serve as fundamental guidelinesfor a rational design of bioinspired water-resistant glue.

CRediT authorship contribution statement

Mengdi Zhao: Methodology, Software, Data curation, Writing -original draft. Liyi Bai: Methodology, Visualization, Validation.Joonkyung Jang: Conceptualization, Methodology, Supervision,Writing - review & editing.

Declaration of Competing Interest

The authors declare that they have no known competing financialinterests or personal relationships that could have appeared to influ-ence the work reported in this paper.

Acknowledgments

This work was supported by the National Research Foundation ofKorea (NRF) grant funded by the Korea government(2018R1A2A2A05019776).

Appendix A. Supplementary material

MD snapshots illustrating the three DOPAs contacting the graphitesurface for conformers 1 and 2 (Fig. S1). Supplementary data to thisarticle can be found online at https://doi.org/10.1016/j.apsusc.2020.145589.

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Underwater adhesion of mussel foot protein on a graphite surfaceIntroductionSimulation methodsResults and discussionConclusionsCRediT authorship contribution statementmk:H1_6Acknowledgmentsmk:H1_9Supplementary materialReferences