Molecular Modeling of Cell Adhesion Peptides on Hydroxyapatite and TiO<sub>2</sub> Surfaces: Implication in Biomedical Implant Devices

doi:10.4236/jbnb.2013.44044

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Journal of Biomaterials and Nanobiotechnology, 2013, 4, 351-356

http://dx.doi.org/10.4236/jbnb.2013.44044 Published Online October 2013 (http://www.scirp.org/journal/jbnb)

351

Molecular Modeling of Cell Adhesion Peptides on

Hydroxyapatite and TiO2 Surfaces: Implication in

Biomedical Implant Devices

Subhashis Biswas1, Udo Becker2

1Department of Chemistry, Narula Institute of Technology, Westbengal University of Technology, Kolkata, India; 2Department of

Earth and Environmental Sciences, University of Michigan, Ann Arbor, USA.

Email: biswass.[email protected]

Received May 28th, 2013; revised June 29th, 2013; accepted July 15th, 2013

License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

ABSTRACT

Molecular modeling as a tool in studying peptide-substrate interactions provides insight on peptide adsorption confor-

mation, adsorption energy, and stability of the peptide-inorganic interface. This work investigates the hydration and

interaction of cell-adhesion peptides, specifically RGD and YIGSR, with the hydroxyapatite surface and TiO2 surface in

cluster and periodic boundary condition approaches. The comparison of adsorption energies of RGD and YIGSR on

both Hydroxyapatite (HA) and TiO2 surfaces reveals the similarities in adsorption energy and orientation pattern of pep-

tides on both surfaces. The models demonstrate that initial peptide orientation affects adsorption energy for both.

YIGSR is consistently more strongly adsorbed to HA-(001) surfaces and steps than RGD for both the surfaces. In addi-

tion, RGD maintained its “hairpin”-like structure during adsorption on a flat HA-(001) surface, and a slightly “relaxed

hairpin” structure on TiO2 (110) surface. Adsorption energies of RGD on TiO2 (110) surface are significantly more fa-

vorable compared to HA-(001) surface, suggesting potential role of TiO2 as biomedical implants when tissue regenera-

tion occurs via cell signaling.

Keywords: Hydroxyapatite; Nanobiomaterial; Bone-Tissue Engineering; RGD; TiO2

1. Introduction

The structure-function properties in bone and teeth are

based on organic-inorganic interactions at the surface,

and these properties are used to design developing func-

tional tissue engineered bone substitutes. Specifically,

the organic-inorganic microenvironment of a biomaterial

surface can influence cellular behavior positively by en-

hancing cell adhesion, spreading, and growth or nega-

tively by promoting cell death, or apoptosis [1]. Bioac-

tive surfaces can incorporate extracellular proteins, cell-

mediated synthetic proteins, or bio-engineered motifs, all

of which interact with the substrate material. This bio-

logical molecule-inorganic mineral interaction can dic-

tate a series of cellular events, including cell-adhesion.

The main goal of bone tissue engineering is to restore

functionality of the damaged tissue. Interactions of or-

ganic molecules such as proteins with inorganic biomate-

rials such as apatite have already been studied exten-

sively. The major challenge is to design a biocompatible

medical device to be inserted inside the damaged tissue

whose growth pattern will be similar to that of protein-

hydroxyapatite interactions.

It is well known that Ti shows a mechanically stable

interface towards bone. The good biological properties

are due to the beneficial properties of the native oxide

(TiO2) that forms on Ti when exposed to oxygen. The

native titanium oxide on Ti is usually amorphous and

very thin, 2 - 7 nm. In addition to being stable in the

physiological environment, titanium oxides increase cal-

cium ion interactions, which are important for protein

and subsequent osteoblast adhesion (osseointegration). It

is therefore essential to know the interaction of protein

molecules with TiO2 which is the starting point of cell

adhesion mechanism that finally leads to bone tissue en-

gineering. In the previous works, interaction of RGD and

YIGSR with hydroxyapatite (001) surface and surface

steps has been studied extensively. It was determined that

initial orientation of the peptide is important regarding

final adsorption energies on the mineral surface. For

example, orientation of the peptides can dictate the sur-

Molecular Modeling of Cell Adhesion Peptides on Hydroxyapatite and TiO2 Surfaces: Implication in

Biomedical Implant Devices

352

face charge of material surfaces, influencing whether

cells will begin to form focal adhesions. The cell-adhe-

sion peptides used in this study were YIGSR (Tyr-Ile-

Gly-Ser-Arg), derived from laminin [2-4], and RGD

(Arg-Gly-Asp), a ubiquitous adhesion peptide [5,6]. The

RGD portion of the hydrated fusion peptide can change

orientation on the hydroxyapatite surface as the fusion

peptide itself binds strongly to the hydroxyapatite surface

during the cell adhesion process. However, the orienta-

tion of the peptide and interaction with surface ions when

adsorbed on the TiO2 surface are unknown. Thus it is

important to calculate the adsorption energies of RGD

and YIGSR with TiO2 surface and compare the results

with the interactions of the same peptides with hy-

droxyapatite surface.

As we know, Computational molecular modeling pro-

vides an alternative to the experimental limitations, and

can provide alternative views of organic-inorganic inter-

actions. Molecular modeling has proven useful for inves-

tigating protein-substrate and peptide-substrate interac-

tions in calcite, calcium oxalate, and apatite systems

[7-12]. Various parameters regarding the interactions of

oligopeptides with biominerals can be deduced from this

type of modeling, such as adsorption conformation, ad-

sorption energies, and stability of the organic-inorganic

interface. Molecular modeling is employed to study in-

teractions between cell adhesion peptides and the hy-

droxyapatite and TiO2 system. The introduction of sur-

face steps can also be included to simulate imperfections

in natural or man-made hydroxyapatite/TiO2 materials.

The goal of this work was to utilize molecular model-

ing methods to investigate the influence of peptide ori-

entation on adsorption of peptides to a hydroxyapatite

mineral surface and TiO2 surface, with the intent to com-

pare the adsorption energies for the interaction of cell-

adhesion peptides with the hydroxyapatite (001) surface

and surface steps along with TiO2 (110) surface. This

was investigated using both a cluster approach and a pe-

riodic boundary condition approach. Specifically, the

aims of this work are to determine the orientation of

RGD and YIGSR when adsorbed to the (110) TiO2 sur-

face and then compare the results with (001) hydroxya-

patite surface with a [010] step. Empirical methods were

used to study the adsorption of these peptides on hy-

droxyapatite surfaces and TiO2 surface using clusters and

periodic surfaces, in addition to studying the hydration

energies of the peptides on hydroxyapatite and TiO2.

2. Computational Modeling Procedures

2.1. Molecular Modeling Set-Up

Using the Cerius2 software, hydroxyapatite (001) sur-

faces and surface steps parallel to [010] were created.

The HYDROXYAPATITE force field was developed

and used to investigate the interactions within the organic

molecules and interactions between each organic mole-

cule and the substrate. This HYDROXYAPATITE force

field is derived from the UNIVERSAL1.02 force field

[13] for the interactions within the peptides, but was al-

tered to accommodate interactions relevant to hydroxya-

patite surfaces and organic molecules. Suitable parame-

ters for three bond intra-atomic potentials, Morse intra

bond potentials and Buckingham interatomic potentials

were obtained by fitting potential parameters to the ex-

perimental structure and physical properties of HA using

GULP [14].

The HYDROXYAPATITE force-field parameters con-

trol the interaction between P and O atoms in the phos-

phate group and the O-P-O angle in the tetrahedral phos-

phate group. These parameters also account for the bond

stretching action between the P and O atoms and intera-

tomic van-der-Waals interaction. The UNIVERSAL1.02

force field does not contain off-diagonal van der Waals

force terms that are necessary to represent the interac-

tions between non-bonded atoms in both the inorganic

and organic layer. Ca2+ ions, P and O atoms in 3



, O

and H atoms in OH− have non-bonded van der Waals

interactions between them. In order to represent these

interactions correctly, non-bonded van der Waals terms

are generated by fitting Lenard-Jones potentials to ex-

perimental constants for these respective atoms. The

above measures are similar to the previous work done in

[15], where adsorption energies of RGD and YIGSR on

hydroxyapatite surface and surface steps are calculated.

Here in this study, interactions of the same peptides on

TiO2 is calculated with TITANIA force field. The nature

of TITANIA and HYDROXYAPATITE force-fields are

almost identical except for few terms that did not require

presence of Ca and P. The Buckingham potential involv-

ing Ca-O, Morse potential involving O-P and the Three-

body potential involving O-P-O is not included in TI-

TANIA force-field, as the interaction of RGD with TiO2

does not require any interactions involving the above-

mentioned atom pairs.

The charge distribution within the peptide molecules,

RGD and YIGSR, was calculated using the QEq charge

equilibration scheme for the neutral peptide molecule

[16]. Molecular dynamics simulations at 300 K were

performed to avoid trapping the adsorbate in a local en-

ergy minimum before and during optimization. These

dynamics simulations were performed using a constant

NVE ensemble. The dynamic time step was 0.001 ps,

and for each molecular dynamics simulation 50,000 steps

were run. These parameters are also similar to the previ-

ous work of RGD-YIGSR interaction with HA, to main-

tain similarity between HA and TiO2 interactions with

Molecular Modeling of Cell Adhesion Peptides on Hydroxyapatite and TiO2 Surfaces: Implication in

Biomedical Implant Devices 353

the peptides. Two different set-ups were used in calcula-

tions involving peptide-HA interactions; a slab with pe-

riodic boundary conditions parallel to the slab and a

cluster that is an atomic equivalent of a hexagonal apatite

prism. For peptide-TiO2 interactions, also both cluster

and periodic boundary conditions are used, but no sur-

face step is created. Four initial peptide start orientations

were used in both set-ups (Figure 1).

2.2. Hydroxyapatite and TiO2 Surface Set-Up for

Simulation

The cluster for hydroxyapatite is chosen in such a way

that there are 76 formula units of Ca5(PO4)3(OH) in the

cluster. Different initial positions of the peptides were

applied 3 - 4 Å away from the flat terrace of the hexago-

nal cluster of the hydroxyapatite. Then, the peptide ge-

ometry was optimized on the cluster with all atom posi-

tions within the cluster being fixed. Finally, the calcium

ions at the top of the hexagonal cluster were allowed to

move during the energy minimization process. This al-

lows the relaxation and movement of calcium ions during

the adsorption of peptides on the mineral surface, better

mimicking the dynamic aqueous environment in in vitro

or in vivo experiments.

Subsequently, a surface step parallel to [010] on the

hydroxyapatite (001) surface was introduced. This step

direction was chosen to keep the cluster stoichiometric

and charge neutral. A small dipole moment perpendicular

to the step was unavoidable in this setup. Peptide adsorp-

tion energies can vary with the starting position and ori-

entation of the peptide along the surface steps. This vari-

ation in adsorption energy occurs because each peptide

has different functional groups at the side chain (of the

amino acids present in them). These side-chain func-

tional groups interact with the mineral surface atoms

differently depending on the orientation of the peptide

with respect to the mineral surface, because different

(a) (b)

Figure 1. Orientation of RGD on (a) Hydroxyapatite and (b)

TiO2 (1 1 0) surface.

atoms of the functional groups are in contact with the

hydroxyapatite surface atoms in different peptide orien-

tations. Thus, variable adsorption energies are obtained

depending upon orientation of the peptide. Four different

starting positions (Figure 1) for the peptide were ob-

served for their final orientation on the hydroxyapatite

surface after energy minimization.

In case of TiO2 (110), the Ti4O8 formulae unit is taken

and the surface has been made with 53 × 53 × 19 Å3 di-

mension with the units separated by 40 Å, which means

there were about 72 formulae units of TiO2.

Calculation of hydration energies was necessary to es-

timate the effective adsorption energy of these peptides

at different orientations on the TiO2 surface. Hydration

energies were calculated for RGD and YIGSR adsorption

on Hydroxyapatite surface in the previous work using

Materials Studio Modeling 4.1 DMol3. It was used to

calculate the extent of hydration on different fragments

of both RGD and YIGSR, as all side chains are not

equally hydrated. For hydration of peptides on TiO2 sur-

face, similar approach has been taken. Here in the hydra-

tion energies calculation, like the previous work, water

was used as a homogeneous solvent with a dielectric

constant of 78.54, and the contribution of the “Cosmo”

hydration energy to the total energy is calculated. “Cos-

mo” approximates the free energy between water mole-

cules and functional groups in peptides. The hydration

energy of the part of the peptides that are hydrated and

those that are on the mineral surface are treated sepa-

rately to correct the calculated in-vacuo adsorption en-

ergy into aqueous hydration energy. This is required for

yielding the effective hydration energy change during the

adsorption of the peptide. Extent of hydration for the

peptide molecules are slightly more in case of TiO2

compared to hydroxyapatite. When adsorption energy of

a peptide is calculated, it is performed according to the

following equation.

ads HA(peptideHA)

peptide in vacuumHAhydration of specific functional groups of peptide

–EE E

















adsTiO peptide TiO

peptide in vacuumTiOhydration of specific functional groups of peptide

E E

E+E+E















3. Results

The adsorption energies for the four different initial ori-

entations of both peptides, RGD and YIGSR, on hy-

droxyapatite and TiO2 (110) surface, are calculated for

cluster and periodic calculations, and the data for cluster

calculations are shown in Table 1 when the surface is

relaxed. For hexagonal cluster calculations, RGD adsorp-

tion energies were low negative values with orientation 4

Molecular Modeling of Cell Adhesion Peptides on Hydroxyapatite and TiO2 Surfaces: Implication in

Biomedical Implant Devices

354

Table 1. Adsorption energies of peptides on Hydroxyapatite

and TiO2.

Peptide orientation

along hydroxyapatite

and TiO2 surfaces

Adsorption energy

on hydroxyapatite

surface Eads HA (eV)

Adsorption energy on

hydroxyapatite

surface eV)

ads TiO

E (

RGD parallel to

Y-axis (Orientation 1) −4.62 −5.03

RGD perpendicular

to Y-axis (Orientation 2) −4.20 −6.63

RGD with open end of

“hairpin” on the surface

(Orientation 3)

−3.53 −6.74

RGD at the edge of the

cluster (Orientation 4) −9.45 −9.83

YIGSR parallel to

Y-axis (Orientation 1) −1.04 −3.67

YIGSR perpendicular

to Y-axis (Orientation 2) −5.52 −8.23

YIGSR with open end of

“hairpin” on the surface

(Orientation 3)

−5.26 −7.23

YIGSR at the edge

of the cluster

(Orientation 4)

−1.52 −5.02

(RGD at the edge and parallel to [010]) being the most

favorable at −3.69 eV. For YIGSR, the hexagonal flat

cluster was the least favorable set-up. Overall, RGD had

lower standard deviations compared to YIGSR when

adsorbed on hydroxyapatite surface. On TiO2 surface,

RGD interacts with the surface atoms mainly via electro-

static interactions along with VDW interaction. YIGSR’s

initial position changes vigorously when brought close to

the surface as initial position on TiO2. The static condi-

tion decreased this fluctuation, whereas when the Ca2+

ions on the top layer of the HA was allowed to move, this

variation increased which is indicative for the different

degree of apatite relaxation during adsorption. For TiO2,

no such variation has occurred.

When the Ca2+ ions were allowed to move during the

simulations on HA surface, a general increase for both

RGD and YIGSR was observed in the adsorption energy

values when compared with appropriate static adsorption

energies. The adsorption of RGD on the terrace of a

hexagonal cluster of the hydroxyapatite (001) face (ori-

entation 1) was −2.64 eV when the atoms in the cluster

are fixed, but this value increased to −4.62 eV when the

Ca2+ ions were allowed to move. In the latter case, the

Ca2+ ions interact with the aspartic acid residue of RGD.

The calcium ions are electrostatically attracted to the

-COO− group in aspartate, which causes the RGD to

move closer to the apatite surface during energy minimi-

zation. The Ca2+ ions relax parallel to the [010] direction

and do not distort the lateral symmetry of the cluster

during relaxation. When RGD was adsorbed on to TiO2

surface when fixed, adsorption energy is −2.95 eV. The

surface energy is increased by many folds when surface

is relaxed, and the RGD retains its near hairpin shape on

the TiO2 surface after simulation.

The hydration energy for relevant functional groups

for both RGD and YIGSR on HA and TiO2 surface are

calculated, respectively, for all set-ups run. Variations in

calculated hydration energies are caused by different

functional groups being adsorbed and the remaining ones

still hydrated after adsorption of the molecule. The re-

sults show that the hydration energy calculated depends

on the peptide orientation with respect to the apatite sur-

face.

4. Discussions

Nanomaterials will replace traditional implants in near

future in the process of tissue-regeneration, where the

cell adhesion peptides with nanomaterial surfaces are the

stepping stone of regeneration process [17,18]. The ad-

sorption of cell adhesion peptides on hydroxyapatite sur-

faces depends on the orientation of the peptide with re-

spect to the hydroxyapatite surface. The dependence of

adsorption energies of the peptides on initial orientation

is a little less on TiO2-surface compared to the HA sur-

face. The adsorption energies vary with the starting ori-

entation of the peptide and are more negative, or more

favorable, when the Ca2+ ions of the top-layer of the

hexagonal hydroxyapatite cluster are allowed to move

during energy minimization. When the cluster is kept

fixed during the simulation, adsorption energies have low

negative values when the RGD is at the step or near the

step edge. Interestingly, RGD maintains its “hairpin”-like

structure when adsorbed to the flat apatite surface. How-

ever, adsorption energies become highly negative and

more favorable for RGD near the step-edge (orientation 4)

when the Ca2+ ions at the top-layer of the cluster are al-

lowed to move (−9.45eV) (Table 1). When a step paral-

lel to the [010] direction on the hydroxyapatite (001)

surface was introduced, adsorption was most favorable

for static conditions when the open end of the RGD

“hairpin” loop is in contact with the surface. When the

peptides are adsorbed onto TiO2 surface, the adsorption

energies are more negative compared to hydroxyapatite

surface for similar initial orientations, which shows that

RGD and YIGSR are more favorable adsorbed on to a

TiO2 surface that RGD surface. The nanomaterial like

behavior of TiO2 surface provides larger surface area for

the peptides compared to HA surface, thus, the adsorp-

tion energies for TiO2-peptide adsorption becomes more

favorable. This also enables on to come to a conclusion

that TiO2 nanomaterial like surface will be more suited

for designing biomedical implant devices where peptides

Molecular Modeling of Cell Adhesion Peptides on Hydroxyapatite and TiO2 Surfaces: Implication in

Biomedical Implant Devices 355

can be adsorbed directly toinitiate the cell-adhesion pro-

cess during bone tissue regeneration process.

The water molecules occupy the adsorption sites on

the hydrophilic TiO2 surfaces, i.e. the water oxygen at-

oms bond to the surface titanium atoms to form the stable

first hydration layer and interact with the surface oxygen

atoms to form the second hydration layer. Besides being

in competition with RGD for the adsorption sites, the ad-

sorbed water layers also play an intermediary role, form-

ing HB interactions with the hydrophilic groups of RGD.

The guanido (NH2), amino (NH3) and carboxyl groups

(COO-) of tripeptide RGD are the main groups bonding

to TiO2 surface by electrostatic and VDW interactions.

The extent of hydration of different functional groups

on each peptide was also considered. Some of the func-

tional groups in the peptide are still hydrated after ad-

sorption and the others are bonded to the mineral surface.

The final adsorbate structure on the mineral surface eva-

luates which functional groups were bonded to the min-

eral surface, and hydration energies of these functional

groups were subtracted from the peptide vacuum adsorp-

tion energy to obtain the effective adsorption energies.

The NH2- with peptide bond elements are more strongly

hydrated than other functional groups (−1.465 eV hydra-

tion energy), followed by the amide functional group

(C(NH)=NH-NH2) of arginine (R) (−1.106 eV). The

COO- groups have hydration energies of ~−0.2 eV to

−0.5 eV. When the peptide is kept parallel or perpen-

dicular to the [010] direction (orientations 1 and 2), the

amide and carboxylic groups interact with the mineral

surface, allowing the peptide to maintain its “hairpin”

position.

The above hydration strategies were used in exactly

same way when adsorption of peptide is calculated only

on HA surface. Adsorption of peptides on TiO2 surface

followed similar course and the hydration energies for

responsible functional groups on TiO2 surface has been

deducted accordingly to calculate the effective adsorp-

tion energy of RGD, YIGSR on TiO2. The retention of

hairpin like structure of RGD on TiO2 surface is of great

importance in showing similarity of behaviour of RGD

on both HA and TiO2-surface in aqueous environment.

5. Conclusion

The adsorption energies of RGD and YIGSR on Hy-

droxyapatite surface and TiO2 surface reveal similar

trends. Comparing the adsorption energies for both the

surfaces, we can conclude that RGD behaves similarly on

both the surfaces, with positioning of the peptide near the

edge of the cluster (Orientation 4) yielding most favor-

able adsorption energy. This gives us a clear idea about

the peptide orientation during the tissue-engineering

process. When artificial inclusion of Titania-based nano-

particles is required inside the tissue, it is important to

know how the peptides are going to interact with TiO2

surface. The adsorption energies and favorable confor-

mations of peptides on TiO2 assist researches to design

biomedical implants making them appropriately keep in

mind that the most favorable surface for peptide adsorp-

tion on TiO2 is (1 1 0). Future studies will concentrate on

more TiO2 surfaces and more peptides to develop a more

general approach for designing of biomedical implants to

facilitate bone-tissue engineering.

6. Acknowledgements

This work has been partially funded by National Science

Foundation, USA, Tissue Engineering at University of

Michigan, NSF Grant of Prof. Udo Becker at University

of Michigan.

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