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.
Received May 28th, 2013; revised June 29th, 2013; accepted July 15th, 2013
Copyright © 2013 Subhashis Biswas, Udo Becker. This is an open access article distributed under the Creative Commons Attribution
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
4
PO

, 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
1
2
3
4
1
2
3
4
(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
–EE E








22
2
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)
2 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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