J. Phys. Chem.

C 2007, 111, 2631-2642 2631

Interaction of Hydrated Amino Acids with Metal Surfaces: A Multiscale Modeling

Description

Pim Schravendijk, Luca M. Ghiringhelli, Luigi Delle Site, and Nico F.A. van der Vegt*
Max-Planck-Institute for Polymer Research, Ackermannweg 10, D 55128 Mainz, Germany
ReceiVed: August 28, 2006; In Final Form: NoVember 7, 2006

We present a multiscale modeling procedure that offers the opportunity to study hydrated biomolecules at
metal surfaces. First principle DFT calculations and classical atomistic simulations are used interactively in
order to account for both quantum and statistical aspects of molecular conformations at the surface. We
present models for water, benzene, phenol, alanine, and phenylalanine at the (111) surface of nickel. These
models are subsequently used in classical atomistic simulations to study physical-chemical aspects of amino
acids at a Ni(111)/water interface. Application of this method to a larger set of “molecular building blocks”
opens a computational route for molecular engineering of bio/inorganic hybrid systems.

I. Introduction develop molecular building blocks whose surface interactions

are carefully parameterized and that can be combined to form
A chemical realistic modeling procedure for describing
any peptide sequence or larger biomolecule. This approach is
peptide interactions with metal surfaces is of considerable
similar in spirit to the development of biomolecular force fields
scientific interest because of a complex interplay of quantum
in which reproducing condensed-phase properties of small
(electronic) and classical (solute and solvent) degrees of freedom
molecules (e.g., resembling the amino acid residues) plays a
that, so far, is only little understood. The ability to model these
key role. In contrast to biomolecular force fields, however, no
interactions in chemically realistic environments can support
general atomistic parameterization can be performed for the
rational procedures for the on-demand design of peptides that
metal surface atoms because the delocalized electrons in the
specifically bind to inorganic surfaces (aptamers). This will help
metal surface will be perturbed differently by different solutes,
the design of bio/inorganic composite materials, for example,
which can only be described with quantum mechanical calcula-
combining optimal solute binding specificity in proteins (e.g.,
tions. The resulting parameter sets describing the interaction of
antibodies) with the optimal signaling properties of inorganic
specific solutes with the metal surface are therefore transferable
materials.1
only for chemical groups with the same chemical composition.
Surface binding up- and down-modulating amino acids in
They can be used to describe any peptide sequence, and
synthetic polypeptides have been identified recently by system-
interactions with the solvent can be incorporated using existing
atic experimental studies.2,3 These studies have only recently
force fields. Obviously, this choice necessarily introduces
become possible because of technical developments such as
approximations, which should be examined carefully whenever
combinatorial peptide engineering4,5 and have opened the way
possible. We assume that the water-surface as well as all
to predict, on an empirical basis, overall protein adhesion by
building block-surface interactions add in a pairwise additive
considering adhesive properties of the constituting amino acids.
fashion. This assumption should be reasonable as long as the
In a previous paper, we outlined a procedure6 suitable to
chemically active groups on the biomolecule have relatively
describe interactions of solvated molecules (i.e., benzene) with
isolated electronic properties (e.g., a polar group in an alkane
transition- and noble-metal surfaces. In the current paper, we
chain). Then, one may combine any number of those groups in
extend upon that work by reporting the interaction of solvated
a macromolecule, as long as the surface-adsorbed groups will
amino acids with a Ni(111) surface. For this purpose, we use
be separated far enough to not disturb the electron distribution
an iterative procedure that converges once the surface interac-
of the neighboring solute-metal interactions.
tions described by the resulting classical model are consistent
with those obtained from first principle quantum calculations, Although the benzene and phenol models discussed in this
in terms of both conformational and energetic aspects. We apply paper can be used as building blocks in peptide sequences, the
this procedure to benzene, phenol, alanine, and phenylalanine. neutral amino acid models discussed in this work do not describe
We, moreover, describe the modeling of water at the metal all features present in peptide bonds. In forthcoming work, we
surface and combine that with the modeling of organic solutes will therefore report the surface interaction of the peptide bond
to study amino acid surface interactions under aqueous condi- (based on a study of n-methyl acetamide), which may then be
tions at 300 K. combined with further models for the amino acid side chain
In view of the chemical complexity of biological molecules, analogs to construct oligopeptides.
as well as the system sizes that can be treated by first principle This paper is organized as follows. After a description of
electronic structure calculations, it would be desirable to develop computational details in Section II, we introduce in Section III
models describing surface interactions of isolated amino acid the modeling procedure and the newly developed models and
residues on a case-to-case basis. This means that we aim to parameter sets for phenol, alanine, phenylalanine, and tyrosine
interacting with the (111) surface of nickel. The modeling
* Corresponding author. E-mail: vdervegt@mpip-mainz.mpg.de. of water-surface interactions, described previously
10.1021/jp065568u CCC: $37.00 © 2007 American Chemical Society
Published on Web 01/23/2007
2632 J. Phys. Chem. C, Vol. 111, No. 6, 2007
in ref 6, will be discussed more extensively in Section III as
well. In Section IV, the newly developed models are used to
study surface interactions under aqueous conditions at 300 K.
II. Computational Details
We extend the “molecular building block” approach that has
already been applied successfully to organic-inorganic inter-
faces.6,7 In this approach, macromolecule-surface interactions
are described at two levels. First, building-block molecules are
chosen that describe the recurring parts in the macromolecule.
The small sizes of these building blocks allow for quantum
mechanical calculations of the building block-surface interac-
tions, and the resulting data are used for parameterizing atomistic
solute-surface interaction potentials. On the other, classical
atomistic, level, this quantum-based parameterization describes
building block-surface interactions, not only for the single
building blocks but also for the structures such as (oligo)peptides
or proteins that can be constructed from combinations of these
building blocks. In the current paper, we will model phenol and
the neutral forms of alanine, phenylalanine, and tyrosine and
study their interaction with a Ni(111) surface from the bulk-
hydrated state. The Ni(111) metal surface has been chosen
because its properties for similar systems have been well-tested
in previous works.6-11 Extension to other surfaces (e.g., Pt, Pd,
Au) is straightforward as will be discussed later on. As an ideal
model surface, any oxidation effects at the surface will be
ignored.
Quantum calculations of the amino acids alanine and phe-
nylalanine have been performed using the DFT based finite-
electronic temperature method of Alavi et al.12 (FEMD), as
implemented in the CPMD code.13 Note that amino acids under
physiological conditions exist mainly (>99%) in the zwitterionic
state, whereas in the case of peptides the end groups are
condensed to form peptide bonds and are therefore of different
chemical nature. The neutral amino acids used here are therefore
not the exact representations of any of those two states but are
still of interest because the neutral state (as well as the
zwitterionic state) has been shown to bind to a Ni(111) surface.14
The zwitterionic state of amino acids as well as the peptide
form are currently under investigation14 and will be a matter of
following publications.
We used the Gromacs 3.3 code,15 adapted to allow for any
combination of atom-wall potentials divided over the molecule,
thus enabling a convenient parameterization of both configu-
rational and energetic data from quantum calculations. Surfaces
are introduced by atom-wall potentials acting in the z direction
at both z borders of the box, and an empty space larger than
any cutoff length is added to remove periodicity in the z
direction. With surfaces at two sides of the box, the system
actually represents a slit; however, the distance between the
surfaces was chosen large enough (>7 nm) to enable a layer of
bulk-like water in the center, several nanometers thick. The box
size in the x and y direction extended 3.4 nm. Pressure coupling
and particle mesh Ewald (PME) treatment of electrostatic
interactions is performed by (semi) two-dimensional schemes
that are part of the Gromacs 3.3 package. Pressure coupling
was chosen to be coupled only to the box size in the x and y
directions, parallel to the surface, and the box size in the z
direction was set constant. The PME Fourier spacing was set
at 0.12 nm, the real space and neighbor search cutoff was set at
0.9 nm, and van der Waals interactions were cut off at 1.4 nm.
Simulations were carried out in a system similar to the one
described in the previous paper,6 consisting of 3000 water
molecules at constant pressure and temperature (NPT) (1 atm
Schravendijk et al.
with a coupling constant of 1.0 ps) (300 K with a coupling
constant of 0.5 ps), using Nose-Hoover temperature coupling16
and Parrinello-Rahman pressure coupling,17 but additionally
introducing the molecules described above and using the LINCS
bond constraint algorithm.18 All simulations were performed
with a molecular dynamics (MD) integration time step of 2 fs.
The solute-surface and solvent-surface potentials were treated
independent from the solute-solute, solute-solvent, and solvent-
solvent intermolecular potentials, which were described by the
GROMOS 43a1 force field.19 As a solvent, the SPC/E water
model was used.20 The natural question arising at this point is
if the use of a specific force field for water causes model
dependencies. We address this question below and show that
this is not the case. In addition to MD simulations, several
Langevin dynamics (LD) simulations (300 K) were performed
in which the solute interacts with the metal surface in a vacuum
environment. The LD algorithm, available in Gromacs,15 was
used with a friction coefficient of 1 ps-1.
Solute-surface potentials of mean force (PMFs) in water
were obtained via constraint-biased simulation with force
averaging21 as provided by the Gromacs package. The constraint
direction was chosen perpendicular to the surface (i.e., in the z
direction). For each PMF, 142 defined constraint distances from
the surface were chosen, in steps of 0.01 nm from 0.19 to 1.00
nm, in 0.02 nm steps from 1.00 to 2.00 nm and in 0.10 nm
steps for distances up to 3.00 nm. In all cases, this proved to
be far enough to reach a bulk-hydrated state of the solute
molecule as indicated by a constant value for the PMF at these
distances. Several constraint sites on the solute molecule were
tested, each separately, to see if any site dependence for the
PMF was present. The following interaction sites were chosen
as constraint sites: for benzene and phenol the geometric center
of the ring; for alanine the carbonylic oxygen and the amine
nitrogen; for phenylalanine the ring center, carbonylic oxygen,
and amine nitrogen. It is important that only the z component
of the constraint site was kept fixed. The constraint site could
move in the xy directions, and the remaining parts of the
molecule could move in any direction as long as this movement
would not displace the z distance of the constraint site.
The starting conformations at the 142 distances mentioned
above were generated by first solvating the molecule in the
middle of the slit, following by pulling it to an adsorbed state
(at z ) 0.19 nm). From there, the z distance was increased in a
sequence of short pull runs. Once all starting points were
generated, 3 ns production runs were performed for each z
distance, enabling the calculation of distance-dependent mean
forces and mean surface interaction energies.
III. Modeling Surface Interactions
The quantum-atomistic multiscale modeling of amino acid-
metal surface interactions is more complex than our previous
multiscale modeling of benzene/polycarbonate adsorption.6,7
This is largely due to the low symmetry and relatively large
number of interaction sites in amino acids and the fact that these
interaction sites are located too close to each other to be treated
separately. The low symmetry greatly affects the number of
quantum calculations necessary: even though alanine has fewer
atoms than benzene, there are many more nonequivalent
geometries in which it can be oriented relative to the surface.
A complete quantum analysis of all of these configurations at
all possible metal lattice sites would require a very expensive
computational effort. An extension to our multiscale modeling
procedure6 is introduced here to cope with the before-mentioned
problems in a way that actually enhances the procedure’s general
validity and applicability.
Hydrated Amino Acids at Metal Surfaces
We start by emphasizing that the attention lies on finding
global minimum energy conformations because these will be
the dominant contribution to the sampling statistics during long
runs at the atomistic level. Calculations on intermediate, higher-
energy states would provide only superfluous information at
the current modeling precision. Therefore, the starting point of
the modeling will be a selection of initial configurations that
aims to give us the extreme binding conformations. The
electronic properties of the metal binding of these configurations
were calculated by a series of quantum density functional
calculations (geometry optimization),14 considering per config-
uration the various possible positions on the metal lattice. The
data retrieved from these calculations give us the parameters
(interaction sites, interaction strength, optimal distances), based
on which an atomistic model is constructed. However, because
we are studying a molecule with a large number of orientational
degrees of freedom, the molecule is likely to get trapped in local
energy minima during quantum calculations. We resolve this
by performing LD simulations of the molecule in vacuum,
applying the modeled molecule-surface interaction parameters,
and sample its configuration space at a range of distances
perpendicular to the surface, using the constraint method and
sites described in the Methodology section. This set of LD runs
can sample a larger amount of the phase space than could be
done by quantum optimization runs, in a fraction of the time.
If the LD simulation generates (only) the surface adsorbing
conformations that were already found in our initial quantum
calculations, then our classical model is considered complete.
If, however, the LD simulation generates adsorbing (low-energy)
conformations that were not previously found in quantum
calculations, then these conformations are used as starting
configurations in a new series of quantum-based structure
optimizations. If this second set of quantum calculations results
in interaction properties that differ from the LD simulations,
then the atomistic modeling is adjusted. Then, the procedure is
repeated (LD run with new modeling, quantum calculation of
LD output), until consistency between the quantum and the
atomistic level is reached and all LD lowest energy conforma-
tions correspond to stable conformations from quantum calcula-
tions with respect to the energy and the configuration.
The newly modeled molecules are introduced below, starting
with phenol which forms a logical extension to the benzene
modeling we performed previously.6 First, however, we describe
the modeling of water at the metal surface.
a. Water. A large amount of research of either experimental
or theoretical nature exists in the field of water-surface
interaction.22-27,29 Recent development in this field focuses on
the aqueous-solid interface.23,25,26 The basics of the atomistic
modeling of the interaction of water with metal surfaces applied
by us has been introduced in a previous publication.6 However,
in that paper we considered only one classical water model.
Here we briefly repeat how the water-surface interaction is
modeled and then proceed further by showing that the relevant
interfacial hydration properties are independent of the classical
water model chosen to describe water-water interactions. To
model the water-surface interaction, we make use of quantum
density functional calculations of small clusters of water
molecules at the metal surface. The water cluster configurations
are chosen by considering all relevant ways for liquid water to
interact with the surface. Examples are shown schematically in
Figure 1.
We base our modeling idea on a well accepted and by now
proven statistical property of liquid water; that is, it is locally
and instantaneously tetrahedral. This allows us to imagine that
J. Phys. Chem. C, Vol. 111, No. 6, 2007 2633
locally at the surface water conformations must consist of full
or half tetrahedra (see Figure 1) because of the confinement of
the surface. Among possible arrangements like the ones shown
in Figure 1, some are not allowed according to data available
from quantum calculations, that is, those conformation display-
ing hydrogen down-like structures. Thus, we have a first
screening of possible conformations that must be reproduced
by our modeling. The second important point is that, because
we want to explore many relevant configurations, we should
carry out many calculations. Because first principles quantum
calculations are computationally very demanding, a solution to
this problem comes from the observation that the tetrahedral
structure of Figure 1 can be described well by different
combinations of substructures consisting of monomers, dimers,
and trimers in different conformations. As shown in Figure 1,
we then make what we would call “the first layer approxima-
tion’’; that is, only the molecule close to the surface and those
directly bonded to that participate to the adsorption strength.
The adsorption energy per water molecule in these allowed
configurations is calculated using a quantum-based approach10
(see the caption of Figure 1 for the calculation used), and the
results are used to parameterize a water-surface potential for
classical simulations. We have chosen an attractive 10-4
potential to describe the interaction between water oxygen and
the surface (see eq 1). No interaction was applied between water
hydrogen and the surface. See Table 1 for exact values of the
parameters used.
{
[52(σz ) - (σz ) ] z e z
10 4
2π10-4
UAttr.10-4 ) cutoff
(1)
0 z > zcutoff
In the classical simulation of the metal-water interface, water-
water interactions are accounted for by a classical force field,
and therefore the energy of water-water hydrogen bonding
should not be included in the water-surface interaction energy.
b. Phenol. Phenol on Ni(111) has a maximum surface
interaction energy that is nearly 15% lower than the maximum
surface interaction energy of benzene (see Table 2 and ref 14).
Its conformation at the surface has the hydroxyl oxygen lifted
by 0.5 Å, which has some effect on the adjacent carbon atom
as well. The hydroxyl hydrogen is pointing down, ending up at
the same height as the phenylic carbon atoms (see Figure 2).
As a basis of the atomistic modeling of phenol, the benzene
model described previously6 is chosen. To describe the interac-
tion with the surface, Morse potentials are used on the aromatic
ring carbon atoms (Cr) (eq 2), and repulsive 10-4 potentials
(eq 3) are used on the ring hydrogens (Hr). The model
parameters are given in Table 1, and atom types are defined in
Figure 3. For all attractive atom types, a zcutoff of 1.4 nm was
used.
{
M(1 - e-a(z-σ))2 - M z e zcutoff
UAttr.Morse ) (2)
0 z > zcutoff
{
[52(σz ) - (σz ) + 53] z e σ
10 4
2π10-4
URep.10-4 ) (3)
0 z>σ
Besides the substitution of one of the hydrogens of benzene
by a hydroxyl group, only a reduction of interaction energy was
needed, which was done by scaling down all carbon-wall
interactions. The carbon next to the hydroxyl group (Cp) was
scaled down to half the interaction energy of the other carbon
atoms (Cr). A weak 10-4 repulsion was put on the hydroxyl
2634 J. Phys. Chem. C, Vol. 111, No. 6, 2007 Schravendijk et al.

TABLE 1: Overview of Molecule-Ni(111) Surface Force TABLE 3: Properties of Four Neutral Alanine
Field Parametersa Conformations That Were Evaluated in Quantum
Mechanical DFT Calculations14 a
interaction potential type  (kJ/mol) σ (nm)
conformation Eads (eV) N (nm) Oc (nm) Cβ (nm)
Water
Ow-Ni attractive 10-4 6.40 0.24 NdownCHup -0.57 0.22 0.32 0.46
Hw-Ni no interaction NdownCHdown -0.32 0.24 0.33 0.36
OdownCHup -0.37 0.46 0.25 0.57
Benzene
OdownCHdown nonbonding 0.39 0.22 0.27
Cr-Ni Morse (a ) 35 nm-1) 17.5 0.20
Hr-Ni repulsive 10-4 4.27 0.20 a
Shown are the adsorption energy on the Ni(111) surface, and the
Phenol atom-to-top Ni layer distance of three of the atoms whose surface
Cr-Ni Morse (a ) 35 nm-1) 15.8 0.20 distance most strongly affects the surface interaction.
Hr-Ni repulsive 10-4 4.27 0.20
Cp-Ni Morse (a ) 35 nm-1) 7.96 0.20 cantly higher than the error margin of the quantum calculation.
Op-Ni repulsive 10-4 1.00 0.25 Currently, no special modeling considerations were made to
Hp-Ni attractive 10-4 0.70 0.22 account for this orientation in the classical atomistic simulation.
Alanine c. Neutral Alanine. Four distinct conformations were used
Oc-Ni attractive 10-4 8.90 0.23 in the initial quantum calculations of neutral alanine, as
N-Ni attractive 10-4 15.0 0.22 described in ref 14. As an example, the strongest binding
CRβ-Ni rep. Morse (a ) 6.0 nm-1) 4.0 0.58
Cv-Ni repulsive 10-4 10.0 0.38 conformation (0.57 eV) is shown in Figure 4; the energies and
R-Ni repulsive 10-4 4.27 0.20 optimal surface interaction site distances of all configurations
Phenylalanine are shown in Table 3. The amine nitrogen (N) and the carbonyl
Oc-Ni attractive 10-4 8.90 0.23 oxygen atom (Oc) interact attractively with the surface. Surface
N-Ni attractive 10-4 15.0 0.22 attraction at these sites is of the order of one to two hydrogen
Hv-Ni repulsive 10-4 4.27 0.17 bond strengths and is modeled with attractive 10-4 potentials.
Cv-Ni repulsive 10-4 10.0 0.38 An interesting feature is the influence of the methyl side-group.
Cr-Ni Morse (a ) 35 nm-1) 17.5 0.20
Even when not directly interacting with the surface, the methyl-
Hr-Ni repulsive 10-4 4.27 0.20
R-Ni repulsive 10-4 4.27 0.20 surface distance is found to influence the total surface interaction
energy. The origin of this influence might be an effect of the
Tyrosine
Oc-Ni attractive 10-4 8.90 0.23 position of the methyl group on the surface orientation of the
N-Ni attractive 10-4 15.0 0.22 interacting amine and carboxyl groups. A simple scheme to
Hv-Ni repulsive 10-4 4.27 0.17 model this effect is chosen that includes a weak repulsive Morse
Cv-Ni repulsive 10-4 10.0 0.38 potential (eq 4) on the center of mass of the CR and Cβ atoms:
Cr-Ni Morse (a ) 35 nm-1) 15.8 0.20 this additional interaction site is referred to as CRβ (see Figure
Hr-Ni repulsive 10-4 4.27 0.20
Cp-Ni Morse (a ) 35 nm-1) 7.96 0.20 3).

{
Op-Ni repulsive 10-4 1.00 0.25
Hp-Ni attractive 10-4 0.70 0.22 M(1 - e-a(z-σ))2 z e σ
R-Ni repulsive 10-4 4.27 0.20 URep.Morse ) (4)
0 z>σ
a
See Figure 3 for the corresponding structures and eqs 1-4 for the
potential functions used. The “R” covers all interactions with no specific The optimal distances (σ values) for these potentials are
interaction with the surface (unlabeled atoms in Figure 3). retrieved from the binding conformations in our quantum
TABLE 2: Ab Initio Interaction Energies and Optimal calculations. Binding energies for the potentials ( values) are
Distances Used to Model Interaction Potentials for Classical chosen such that the sum of all site-surface potentials (eqs 1-4)
MDa acting on the molecule will reproduce the total surface interac-
interaction Eads (eV) dopt (nm) tion energy as found in the quantum calculation, for every
conformation tested. Atoms with no specific surface interaction
water-Ni 10
-0.25 0.24
benzene-Ni 44 -1.05 0.20 were given a simple repulsive 10-4 potential (with parameters
phenol-Ni 44 -0.9 0.20 (ring) based on the repulsive hydrogens in the benzene ring, see group
Ala-Ni -0.57 0.22 (N) R in Table 1) to prevent the occurrence of unphysical conforma-
Phe-Ni 9 -1.1 0.20 (ring) tions corresponding to a penetration of the surface. The first
a
For neutral phenylalanine (Phe-Ni), only the optimal configuration iteration of this modeling resulted in minimal energy LD
was evaluated. For neutral alanine (Ala-Ni), the energy of the conformations that had both the amino nitrogen and the carbonyl
configuration with highest surface interaction is given. A complete oxygen interaction sites at optimum distance. The total surface
overview is given in Table 3. interaction energy corresponded to the sum of both interactions.
Consecutive quantum calculations of the LD output structures
oxygen (Op), and an attractive 10-4 potential (see eq 1) was showed that this was actually a nonbonding conformation.
put on the hydroxyl hydrogen (Hp). Consequently, a modification of our initial modeling was needed
Configurations of phenol with the OH group pointing away to ensure that only one interaction site at a time will be able to
from the surface did not need to be taken into account in QM bind with optimal interaction energy. This was reached by
calculations, because the perturbing effect of the OH group will introducing a repulsive site (Cv) at a position between the amino
be lower the further it is away from the surface, and any nitrogen and the carbonylic oxygen (at 40% of the bond length
interaction would be similar to the inclination dependence of between carbonylic carbon and CR, see Figure 3), leading to a
benzene modeled previously.6 The configuration where phenol seesaw-like mechanism that allows for the binding of either the
is pointing with the OH group toward the Ni(111) surface is amino or the carbonyl group. LD runs with this modeling lead
currently being investigated by quantum calculations.30 Pre- to optimal configurations close to the previous quantum
liminary calculations indicated a weak interaction, not signifi- calculations, see Figure 5, and this modeling was therefore
Hydrated Amino Acids at Metal Surfaces J. Phys. Chem. C, Vol. 111, No. 6, 2007 2635

Figure 1. Graphical aid showing the rationale behind the ab initio modeling. The water configurations studied by quantum mechanic DFT calculations
were chosen by considering all relevant ways for liquid water to interact with the surface. Some examples are schematically shown here. In white
circles are tetrahedral water substructures at the water-metal surface. I: A possible tetrahedral water structure with two waters interacting with the
metal surface. II: A trimer, the upper part of a tetrahedral water structure, with one water interacting with the metal surface and two additional
hydrogen-bonded water molecules. III: One of many configurations that could be discarded immediately because no electronic hydrogen-metal
interaction exists. The isolated water tetrahedron is an unstable structure, both in vacuo and metal-bound. Therefore, ab initio calculations are done
with smaller subunits. In DFT calculations, we can represent the tetrahedral structures shown in I and II by using all relevant water structures
consisting of (A) a water monomer, representing one of the symmetry axes of the tetrahedron; (B) a water dimer, representing the metal-bound
water with its first hydrogen-bonded neighbor (the tetrahedral center); (C) a water trimer, directly representing structure II. The bare water-metal
interaction energies (excluding contributions of H2O-H2O hydrogen bonding) are calculated as Eads ) E(surf+Nmol) - Esurf - ENmol, where Nmol refers
to the number of water molecules in the system, E(surf+Nmol) denotes the QM energy of the combined surface + water substructure, Esurf is the QM
energy of the isolated metal surface, and ENmol is the energy of the isolated water substructure. Eads/NH2O equals 0.25 ( 0.05 eV on Ni(111) independent
of NH2O ()1, 2, or 3). The complete overview of all conformations evaluated in quantum density functional calculations is given in ref 10.

ring could reach their positions of maximum interaction energy,

Figure 2. Minimal energy phenol configuration when adsorbed on
Ni(111), as found by quantum calculations.44 The green area represents
the location of the nickel surface.
chosen for our MD production runs. The final potential
parameters are given in Table 1. Note that even though only
one point (minimized energy) per conformation is used, the fact
that we use four different conformations for our potential fit,
with various groups interacting simultaneously for every
conformation, makes this more elaborate than a one-point
parameterization.
d. Neutral Phenylalanine and Tyrosine. Phenylalanine and
tyrosine can, in a building block manner, be constructed by
combining characteristics of the alanine and the benzene/phenol
modeling. The repulsive CRβ site, present in the alanine model,
is discarded in the phenylalanine and tyrosine models. Instead,
because repulsive aliphatic hydrogen atoms proved to be a
necessary modeling element to prevent unphysical conforma-
tions with Cβ hydrogens penetrating the surface, these were
introduced (one on the CR, two on the Cβ) as virtual sites in the
phenylalanine and tyrosine molecules. We use the terminology
“virtual” sites because, apart from experiencing surface repul-
sion, they do not interact with the solvent; in the GROMOS
43a1 force field19 hydrogens connected to aliphatic CR and Cβ
carbons are absorbed into united-atom potentials centered on
the carbon positions. Interactions of other atoms (e.g., solvent)
with these aliphatic CHn groups are described using these united
atom potentials. Virtual sites in Gromacs are built from the
coordinates of 2, 3, or 4 vicinal atoms; any forces on the virtual
sites are spread out over these atoms at the end of each time
step. The bond lengths and angular potentials of our virtual sites
were taken from the all-atom OPLS force field.31 In the resulting
lowest energy conformation obtained from LD simulations in
vacuum, we found that both the amine nitrogen and the phenyl
leading to a total surface interaction energy of 1.59 eV (153
kJ/mol). This is different from the initial quantum calculation
corresponding to a 1.1 eV binding conformation, where the
amino and carboxyl group were chosen to point away from the
surface, to minimize surface contact of the aliphatic Cβ
hydrogens.9 Following our iterative multiscale modeling pro-
cedure, we tested the lowest energy LD conformation in a
consecutive quantum calculation,32 and it was found to be a
stable conformation (1.5 eV). One aliphatic Cβ hydrogen is close
to the surface but can apparently find a stable position within
a hollow site of the surface. Because the optimal LD interaction
energy and conformation were close enough to the optimal
conformation found by quantum calculations (within the 0.1
eV error of the quantum calculation), no further optimization
of the modeling was needed. The final combination of atom-
surface potentials is given in Table 1 and Figure 3.
IV. Analysis of Surface Interactions at the Ni(111)/H2O
Interface
For benzene and phenol, an in-depth analysis can be made
of the surface interaction mechanism under aqueous conditions.
Because of the high symmetry of the benzene ring, its center-
of-mass-surface distance was recently shown to provide a
logical choice for an order parameter along which a free energy
can be calculated,6 by which the surface interaction can be
characterized. When extending this analysis to a phenol
molecule, we meet with a slightly broken symmetry; we can,
however, still take the distance between the geometric center
of the ring and the surface as the order parameter of interest.
For benzene and phenol, their planar structures enable us to
study not only the PMF’s z-dependency but also the surface
inclination dependence described by the angle between the
normal of the aromatic ring and the normal of the surface, at a
given z distance, as will be discussed in more detail below.
Following the surface interaction mechanisms of hydrated
amino acids is more problematic, not only because of their low
symmetry as compared to a benzene ring but also because of
their many degrees of conformational freedom and various
interaction sites. Therefore, several order parameters can be
2636 J. Phys. Chem. C, Vol. 111, No. 6, 2007
Figure 3. Atom types used in Table 1. Shown are (A) benzene, (B)
phenol, (C) water, (D) neutral alanine, (E) neutral phenylalanine, and
(F) neutral tyrosine.Atom names refer to the atom names in Table 1.
The sites CRβ and CV are specially introduced for the current
modeling: CRβ is a virtual site located exactly at the center of mass of
CR and Cβ. CV is a repulsive virtual site needed to prevent simultaneous
adsorption of the N and carbonyl O (OC) atoms within the same
molecule, as explained in the text. Note that the water hydrogens (HW)
do not have any interaction with the surface. Unlabeled atoms have
the general repulsion “R”.
chosen to follow the process, all of which will, however, be
interdependent: at any surface distance of a given interaction
site, all other interaction sites will contribute to the PMF at that
particular distance. Here, we limit ourselves to presenting only
the free-energy difference between the bulk-hydrated state and
a selection of local free-energy minimum states with strong
surface interaction, and a description of the interaction energies
involved. To better understand hydration effects, we will also
compare the explicit solvent MD simulations with the LD
simulations of the amino acids in vacuum that were performed
during our modeling procedure. The total combination of relative
surface interaction energies for the various amino acids, and
comparisons of surface interactions under solvated and non-
solvated conditions, can give essential information to help us
understand the main chemical factors that determine metal-
surface interaction of amino acids, and in this way facilitate
the design of surface-binding peptides.
a. Water. We used our water modeling procedure to describe
the Ni(111)/water interface using different classical water mo-
dels. Applied were the three-site SPC,33 SPC/E,20 and TIP3P34
models, the four-site TIP4P34 model, and the five-site TIP5P35
model. For each water model, we studied the water structure at
the surface and the benzene-surface and phenol-surface
Schravendijk et al.
Figure 4. One of the four alanine-Ni(111) conformations as men-
tioned in Table 3. Main characteristics of this conformation (Ndown-
CHup) are the binding of the amine nitrogen to a top site of the Ni(111)
surface and the methyl group pointing away from the surface. The
carbonylic oxygen is pointing slightly toward the surface. A detailed
quantum analysis of this and other structures is given in ref 14.
potential of mean force based on simulations of one solute
molecule in water.
Figure 6 compares the water structure near Au(111) and Ni-
(111) for the SPC, SPC/E, TIP3P, TIP4P, and TIP5P water
models. The water-metal interaction for Ni(111) amounts to
0.25 eV per molecule (24.1 kJ/mol) at an optimal distance of
2.4 Å; for Au(111) it amounts to 0.10 eV per molecule (9.7
kJ/mol) with an optimal distance of 3.1 Å.6 Clearly, the structure
of the metal-water interface is independent of the classical
water model. On Ni(111) the hydrogen density profile (dashed
line) is highly structured (four peaks for z < 7Å) because
hydrogen atoms belonging to water molecules in the first
adsorbed water layer either correspond to OH bonds aligning
the surface or OH bonds hydrogen bonded to water molecules
in the second adsorbed layer. Hydrogens belonging to water
molecules in the second water layer, in turn, donate hydrogen
bonds to waters in the first layer and water molecules in the
bulk. On Au(111) the hydrogen density profile is less structured,
indicating reduced hydrogen bonding between the water layers.
The peak height for the first water layer on Au(111) is in the
order of 1/3rd of the peak height of the first water layer on
Ni(111). The relative peak heights are, however, not a good
measure of the relative water densities at the Au(111) and Ni-
(111) surfaces because these peaks are narrower than the
molecular diameter of water and the density varies rapidly over
this range. Therefore, we integrated the water (oxygen) density
profile over the first peak up to the first minimum. The resulting
number, expressed in units area per molecule, is given in Table
4 for all five water models. For Au(111), surface areas in the
range of 9.3-9.9 Å2 per molecule were found, for Ni(111) the
range was 8.4-8.9 Å2 per molecule. Note that these values are
in the same order as those reported by Shelley et al.28,29 for
atomistic simulations of a water slab near Hg surfaces.
Different water models produce only small differences in the
structure of the metal-water interface, independent of the
Hydrated Amino Acids at Metal Surfaces J. Phys. Chem. C, Vol. 111, No. 6, 2007 2637

Figure 5. Justification of the atomistic modeling. Solid line: average

alanine-surface interaction energy (A and B) and site-surface distance
(C and D) obtained from a series of 3 ns constrained LD simulations
in vacuum at 300 K. Dots: optimal energy (A and B) and optimal
distance (C and D) of zero-temperature quantum calculation optimized
structures. In part C, the distance of the carbonylic O is shown (vertical
axis) for a given constrained distance of the amino N (horizontal axis).
In part D, the distance of the amino N (right vertical axis) is shown
for a given constrained distance of the carbonylic O (horizontal axis).
The LD data (solid lines) were obtained by constraining either the N
or the O surface distance in the simulation. The distances and
corresponding energies from the quantum calculations are all retrieved
from the three binding configurations found in quantum calculations.14
The atomistic model samples the quantum-based conformation and
energy either correctly or within a 0.05 nm distance. Parameters for
this modeling are mentioned in Table 1. Figure 6. Normalized water densities near Au(111) (top graph) and
Ni(111) (bottom graph) for SPC,33 SPC/E,20 TIP3P,34 TIP4P,34 and
strength of the water-metal interaction. This is an additional TIP5P35 water models. Solid line, water oxygen; dashed line, water
confirmation that the current modeling procedure allows for a hydrogen.
separated treatment of molecule-surface interactions while
using existing force fields for molecule-molecule interactions. TABLE 4: Surface Area Per Water Molecule in the First
b. Benzene and Phenol. Both the benzene and phenol Adsorbed Layera
z-dependent PMFs (Figure 7) are qualitatively very similar. The area per molecule (Å2)
structural details of the PMFs follow the water oxygen density water model Au(111) Ni(111)
fluctuations (Figure 6). Upon approaching z ) 0.5 nm (corre- SPC 9.52 8.64
sponding to the position of the second oxygen peak in the water SPC/E 9.27 8.37
density profile) from larger distances, the benzene (phenol) TIP3P 9.46 8.61
molecule starts to expel water from the second water adsorption TIP4P 9.61 8.79
layer and the PMF increases rapidly. The PMF profiles correlate TIP5P 9.86 8.92
with the water density data from Figure 6, where we can find a Determined by the integral of the oxygen density peak adjacent to

a first water layer around z ) 0.2-0.3 nm, a second water layer
around z ) 0.5-0.6 nm, and a very weak third water layering
around z ) 0.8-0.9 nm.
Our previous paper6 showed that the potential of mean force
(PMF) for displacing a benzene molecule from bulk water to
the surface not only gives an idea about adsorption/desorption
energies and intermediate energy barriers but also helps in
understanding the critical steps in the adsorption/desorption
mechanism.6 Any crucial effect that the choice of classical water
model would have on the adsorption mechanism would therefore
be visible in the corresponding PMF. Figure 7 shows that with
all classical water models similar features are observed in the
PMF, with a major free-energy barrier (50-60 kJ/mol high)
starting almost directly at the surface (0.20 nm), ranging until
ca. 0.60 nm. Additional oscillations occur further away from
the surface up to ca. 1.50 nm. Differences are found in the
barrier heights and the free-energy difference between the bulk-
the surface in Figure 6.
hydrated (z > 3 nm) and surface-adsorbed state (z ) 0.2 nm).
These variations are partly accounted for by the error margins
of these PMF calculations (between 4 and 8 kJ/mol at z ) 0.2
nm), see the caption of Figure 7, and small differences in water
densities at the surface. In addition, differences in bulk water
density and solvation free energies for the various water
models36-40 are likely to be a source for variations in the
resulting free-energy difference.
In Figure 8A, two-dimensional PMFs for benzene and phenol
are shown as a function of z and the inclination angle between
the aromatic ring- and surface normals. A selection of snapshots
of benzene at various surface distances is provided in Figure
8B. In this two-dimensional free-energy landscape, a more
detailed picture is shown, and we can subdivide several zones
when approaching the surface (z ) 0.2 nm) from the bulk
2638 J. Phys. Chem. C, Vol. 111, No. 6, 2007 Schravendijk et al.

Figure 7. Solute-surface PMFs for displacing the geometrical center of the phenyl ring of (A) benzene and (B) phenol perpendicular to a Ni(111)
surface, in liquid water (300 K) described with five classical water models. PMFs were obtained by integrating the average constraint force on the
solute center of mass along 140 discrete points between 0.20 and 3.00 nm from the metal surface. At each point, 3 ns MD runs were performed
to sample the mean constraint force. Solid black line, SPC water;33 dashed black line, SPC/E water;20 dashed/dotted black line, TIP3P water;34 solid
gray line, TIP4P water;34 dashed gray line, TIP5P water.35 The errors of these PMF calculations ranged between 4 and 8 kJ/mol at z ) 0.2 nm and
were estimated by calculating the block average error estimate45 for every constraint distance and taking the square root of the integral of the square
of all error estimates from bulk (z ) 3.0 nm) toward the closest distance to the surface that was sampled (z ) 0.20 nm).

solvent (z > 1 nm). In the bulk zone going from z > 1 nm
toward z ) 0.8 nm the sampling is distributed evenly over all
angles. For benzene (less clear for phenol), it can be seen that
around 0.7 nm (in between the third and second water layer;
see Figure 6) already some structural effects occur and the
parallel conformation (cos(θ) ) 1) is slightly less sampled. At
distances corresponding to the second adsorbed water layer
(between z ) 0.6 nm and z ) 0.5 nm), benzene (phenol)
preferentially orients parallel to the metal surface. (The distribu-
tion of cos(θ) is narrowed down to 0.9-1.0 in Figure 8A. A
snapshot of the parallel conformation can be seen in Figure 8B,
at 0.49 nm.) This orientation is favored energetically because
of O-H‚‚‚π hydrogen bonding involving water molecules in
the first and second surface hydration layers. This type of weak
water-aromatic hydrogen bonding is described properly by the
force field.41 In Figure 7, this causes a shoulder to appear in
the PMF at z ) 0.58 nm. A rather flat landscape with respect
to the orientational degree of freedom is found in the region
between the second and first adsorbed water layer (0.4 nm < z
< 0.5 nm). Although, toward z ) 0.4 nm, perpendicular
orientations are favored in comparison to parallel ones. In Figure
7 a shoulder is observed at these distances, and in Figure 8B
one can see how a perpendicular orientation minimizes the
displacement of water molecules in both the first and second
adsorbed water layer. As the geometrical center of the ring
approaches the first adsorbed water layer, the benzene (phenol)
ring normal gets significantly tilted with respect to the surface
normal and finally lines up with the surface normal, driven by
an energetic stabilization of 1 eV due to the overlap of benzene-
(phenol)-π-orbitals with free electrons in the surface. In this
process, first layer water molecules are expelled from the
hydrophilic nickel surface, even before significant benzene-
(phenol)-surface binding interaction is present. It is clear that
if the benzene would adsorb in a solvent-free environment then
the z-dependent angular distribution plot would show a random
orientation for distances of ca. 0.5 nm and higher and would
show a similar profile to the solvated state only for short
distances below 0.3 nm, because here the orientation of the ring
is governed by the presence of the surface.
c. Amino Acids. To study surface-interacting amino acid
conformations, we performed several MD runs in which a single
interaction site-surface distance (order parameter) was con-
strained and a PMF as a function of that order parameter was
obtained by integrating the mean force starting from z ) 3 nm
downward toward the surface. Using this method, the distances
with minimal free energy were determined. Snapshots of
corresponding conformations as well as the average surface
interaction energies and relative free energies (as compared to
z ) 3 nm) at these distances are shown in Figure 9.
Comparison of the free energies in Figure 9A and B as well
as Figure 9C and D shows that, independent of whether the
distance constraint is applied on the oxygen or nitrogen, similar
values are obtained, which is an indication that sufficient
sampling has been reached. The snapshots show that the amino
acid conformations in Figure 9A and B as well as those in Figure
9C and D are similar. The free energies for phenylalanine
viewed from the amino N (Figure 9C) and carbonylic O (Figure
9D) order parameters are lower than those for the alanine cases
(about 9 kJ/mol). This is rather counterintuitive because the
bulky phenyl ring did not contribute to the surface interaction
energy for these order parameters, but intuitively its excluded
volume can be assummed to displace more water molecules
from the surface as compared to the methyl group from alanine.
An explanation could be that in the case of alanine the small
methyl group is able to come close to the surface, thereby weak-
ening the interaction of amine and carbonyl groups. In contrast,
the bulky phenyl group of phenylalanine will not be able to
pass the hydration layers present at the surface and therefore
will not hinder binding of the amine and carbonyl groups.
Hydrated Amino Acids at Metal Surfaces J. Phys. Chem. C, Vol. 111, No. 6, 2007 2639

Figure 8. (A) Two-dimensional PMFs for benzene (left) and phenol (right) at Ni(111) in SPC/E water (300 K). The solute (center-of-mass)-to-
surface distance is plotted vertically; the cosine of the angle between the solute- and surface normal vectors is plotted horizontally. The 2D-PMF,
G(z,θ) ) G(z) + G(θ|z), was calculated from constrained MD. By applying a constraint to keep the z coordinate fixed, G(z) (see Figure 7) is
obtained by integrating the mean constraint force along the z coordinate. G(θ|z) ) -kBT lnP(θ|z) is obtained from the conditional distribution
function, P(θ|z), sampled in the constrained MD runs. (B) Benzene snapshots at a selection of center-of-mass constraint distances from the surface.

The large positive free energy obtained by displacing the
phenyl ring in phenylalanine toward the surface (Figure 9E)
requires additional comments. This conformation has the lowest
total solute-surface interaction energy of all structures that
interact with the surface as found here, but it is the least
favorable from a free-energy point of view (∆Gads ) +32.6
kJ/mol ( 19.8 kJ/mol). A reasoning to explain this observation
would be to consider the fact that transferring the ring to the
surface requires a displacement of more water molecules than
in all other cases. In Figure 10 the surface interaction energies
for water, phenylalanine, and the interaction sites of phenyla-
lanine are plotted against the distance of the constrained center
of mass of the phenyl ring. The contribution of water-surface
interactions decreases over the distance from bulk to optimal
adsorption with 140 kJ/mol, about 70 kJ/mol more than for the
other cases, where, instead of the phenyl ring, the O or N
interacts with the surface (data not shown). One can get an
impression of this solvent effect when comparing the pheny-
lalanine surface interaction in explicit solvent MD (Figure 9E)
with LD runs in vacuum (Figure 9F), where we find free-energy
minima at the same distance (geometrical center of the ring at
0.22 nm), similar interaction energies (-134.7 kJ/mol in explicit
2640 J. Phys. Chem. C, Vol. 111, No. 6, 2007 Schravendijk et al.

Figure 9. Snapshots of amino acids and parts of the surrounding water at the free-energy minimum distance of the constraint sites chosen, determined
by the PMF method as explained in the text. Eint denotes the sum of interaction energies for all solute interaction sites with the surface. ∆G denotes
the free energy of surface interaction, taken by the difference in the PMF between the distance given here, and the bulk state at z ) 3.0 nm. Error
bars are calculated by calculating the block average error estimate45 for every constraint distance and taking the square root of the integral of the
square of all error estimates from bulk (z ) 3.0 nm) toward the constraint distance mentioned here. ∆G for a given molecule is found to be
independent of the interaction site (within the error of the calculation) and dramatically dependent on the presence of water. (A) Alanine, amino
N constrained at z ) 0.24 nm. (B) Alanine, carbonyl O constrained at z ) 0.28 nm. (C) Phenylalanine, amino N constrained at z ) 0.24 nm. (D)
Phenylalanine, carbonyl O constrained at z ) 0.29 nm. (E) Phenylalanine, geometrical center-of-ring constrained at 0.22 nm. (F) As in part E, but
taken from an LD simulation in vacuum.

solvent MD and -137.8 kJ/mol in vacuum LD), but largely
different free-energy values (+32.6 kJ/mol in explicit solvent
MD vs -93.3 kJ/mol in vacuum LD). By looking at the water-
and solute-surface interaction energies in Figure 10, it is
apparent that a competition between water and nitrogen plays
an important role: every increase in solute-surface interaction
energy is accompanied by a decrease of water-surface interac-
tion energy and vice versa.
The similarities in the surface interaction mechanism of
phenol and benzene (Figure 8) indicate that the tyrosine-surface
interaction is similar to that of phenylalanine.
V. Discussion
Four factors are necessary at the level of computer simulations
in order to get a complete theoretical picture of peptide
adsorption on metal surfaces. First, any molecule-metal surface
interaction has to be parameterized by ab initio methods and
cannot be represented by generalized force fields. An efficient
procedure to obtain a correct parameterization is presented in
the current paper. The second factor is related to the competitive
adsorption energies of the solvent and solute, where one should
take into account the number of solvent molecules that have to
be displaced by the solute.6,42 It has become apparent, however,
that taking these competitive effects alone does not provide the
full description of the system because it does not properly
account for solute hydration and the surface hydrophilicity.6 This
is the third factor that should be taken into account: depending
on surface hydrophilicity, dense adsorbed water layers may exist
close to the surface. Intrusion of these mutually hydrogen-
bonded layers causes energy barriers for surface approach.
Therefore, explicit solvent (atomistic) simulations are necessary,
using timescales long enough to allow for solvent rearrange-
ments. The fourth factor concerns the geometry and orientation.
Especially for longer molecules like polypeptides, many con-
formations exist next to the surface and a correct sampling has
Hydrated Amino Acids at Metal Surfaces
Figure 10. Dependence of surface interaction energies (averaged over
3 ns simulations) of phenylalanine and water on the phenyl-ring-surface
z-distance at 300 K. Shown are the overall solute-surface interaction
energy (blue line), the water-surface interaction energy (green line,
right vertical axis), phenyl ring-surface interaction energy (red line),
and amino nitrogen-surface interaction energy (brown line). Water is
expelled as the ring approaches the surface, causing a loss in water-
surface interaction energy of approximately 140 kJ/mol over the distance
from 0.75 to 0.20 nm. Over the same distance the solute gains a
maximum of 130 kJ/mol at 0.22 nm (see snapshot E in Figure 9). The
statistical noise in the water-surface and solute-surface interaction
energy profiles is correlated due to a competition of water and amino
nitrogen binding. The large statistical uncertainty (19.8 kJ/mol) in the
free-energy calculation (snapshot E in figure Figure 9) is due to the
noisy energy profile. The free-energy barrier in Figure 7 can be
explained from the water-surface and solute-surface interaction
energies: for 0.35 nm < z < 0.6 nm the water-surface interaction
energy decreases and is not compensated by an increase of solute-
surface interaction energy.
to be performed to find all possible surface-interacting confor-
mations. Because of solvent effects, the outcome may well be
non-trivial.
The multiscale simulation approach presented here combines
configurational and chemical information needed for engineering
surface-interacting peptides. The simulations provide insight into
the mechanisms of surface interactions in hydrated systems and
can therefore directly be applied to support and explain
observations in experimental studies. Obviously, the approach
described here requires extension. QM calculations of the
peptide group (CONH) and water interacting with Pt surfaces
are currently being performed by us. Future work on additional
modeling of amino acid residue interactions with this surface
will result in a molecular construction set opening the way to
the modeling of a variety of peptide-surface systems.
Amino acid interactions with the nickel surface modeled in
this work are transferable to surfaces of different chemical
composition. The surface interaction energies of benzene and
water can be arranged as a series with comparable energies for
Ni, Pt, Pd, and Rh.6 Therefore, the mechanisms described here
for nickel are likely to be similar on Pt, Pd, and Rh. Several
preliminary generalizations comparing our modeling with
experimental results can then be made. First of all, our
simulations explain why phenylalanine, for which QM density
functional calculations indicate that it binds strongly to a metal
surface (i.e., Ni, Pt, Pd), is not found within the strong metal
binders experimentally.2,3 The strongest binding configuration
of a phenylalanine molecule in vacuo (the interacting aromatic
ring oriented parallel to the surface) is shown by us to
correspond with a highly unfavorable free energy when in the
presence of solvent (Figure 9). Although in our simulations
phenylalanine is a better binder than alanine (contrary to
experimental findings on oligo-peptides2,3), one has to take into
account that our simulations concerned only single amino acids.
We will at a later point extend our simulations to peptide chains,
J. Phys. Chem. C, Vol. 111, No. 6, 2007 2641
for which different behavior may be observed. Tyrosine is
experimentally found to be a relatively strong binder among
the uncharged amino acids.2,3 Because our simulations showed
that the planar-ring conformation is unlikely to bind to a
hydrated surface, the most reasonable explanation will be an
interaction of the phenol hydroxyl group in tyrosine with the
metal surface. Because of electronic polarization effects, surface
defects might contribute to this interaction. Here it should also
be kept in mind that in most experiments polycrystalline noble
metals are used;2,3 hence, interactions with alternative crystal
planes and surface defects require attention in future calculations.
We note that QM density functional calculations of the
adsorption of water10 and benzene43 on metal surface defects
have already been performed recently.
VI. Conclusions
We have reported an iterative multiscale modeling procedure
that uses (1) quantum density functional calculations to obtain
surface interaction energies and optimum distances and (2)
classical atomistic simulations to overcome energy barriers and
guide localizing global conformational minima. After consis-
tency between the atomistic modeling and the quantum calcula-
tions has been reached, the fast sampling obtainable with
atomistic simulation is used to investigate interactions of
biological molecules with metal surfaces in water. Following
this approach, it is now possible to take into account electron
delocalization effects in interactions of amino acids with metal
surfaces and to fully consider the water-solute and water-
surface interactions present in hydrated systems. These advance-
ments are essential in approaching a realistic modeling of
experimental peptide-surface systems. As an application, the
multiscale modeling of hydrated phenol, alanine, phenylalanine,
and tyrosine has been performed, and various adsorption
properties (adsorption energy, free energy, structural informa-
tion) have been obtained.
Several general conclusions concerning the chemistry of
surface adsorption can be drawn from the current study. Most
importantly, it is found that quantum-based binding energies
alone do not suffice to understand the thermodynamic aspects
of protein-surface interactions. Instead, one should account for
the competing effects of solvent and other adsorbing groups,
potentially introducing free-energy barriers for surface approach.
Additionally, our multiscale modeling can be applied to study
geometrical effects in detail, as exemplified with our analysis
of benzene and phenol, which can help in understanding the
kinetics of adsorption processes.
Acknowledgment. We thank Kurt Kremer, Matej Praprot-
nik, and Hatice Duran for helpful discussions.
References and Notes
(1) Sano, K.-I.; Sasaki, H.; Shiba, K. Langmuir 2005, 21, 3090.
(2) Peelle, B. R.; Krauland, E. M.; Wittrup, K. D.; Belcher, A. M.
Langmuir 2005, 21, 6929.
(3) Willet, R. L.; Baldwin, K. W.; West, K. W.; Pfeiffer, L. N. Proc.
Natl. Acad. Sci. U.S.A. 2005, 102, 7817-7822.
(4) Brown, S. Nat. Biotechnol. 1997, 15, 269.
(5) Whaley, S. R.; English, D. S.; Hu, E. L.; Barbara, P. F.; Belcher,
A. M. Nature 2000, 405, 665.
(6) Schravendijk, P.; van der Vegt, N.; Delle Site, L.; Kremer, K.
ChemPhysChem 2005, 6, 1866.
(7) Delle Site, L.; Abrams, C. F.; Alavi, A.; Kremer, K. Phys. ReV.
Lett. 2002, 89, 156103.
(8) Abrams, C. F.; Delle Site, L.; Kremer, K. Phys. ReV. E 2003, 67,
021807.
(9) Delle Site, L.; Kremer, K. Int. J. Quantum Chem. 2005, 101, 733.
2642 J. Phys. Chem. C, Vol. 111, No. 6, 2007
(10) Sebastiani, D.; Delle Site, L. J. Chem. Theory Comput. 2005, 1,
78.
(11) Murakhtina, T.; Delle Site, L.; Sebastiani, D. ChemPhysChem. 2006,
7, 1215.
(12) Alavi, A.; Kohanoff, J.; Parrinello, M.; Frenkel, D. Phys. ReV. Lett.
1994, 73, 2599.
(13) Hutter, J.; Alavi, A.; Deutsch, T.; Bernasconi, M.; Goedecker, S.;
Tuckerman, M.; Parrinello, M. CPMD V. 3.4.1, 1995-1999.
(14) Ghiringhelli, L.; Schravendijk, P.; Delle Site, L. Phys. ReV. B 2006,
74, 035437.
(15) van der Spoel, D.; Lindahl, E.; Hess, B.; Groenhof, G.; Mark, A.;
Berendsen, H. J. C. J. Comput. Chem. 2005, 26, 1701.
(16) Nosé, S. Mol. Phys. 1984, 52, 255.
(17) Parrinello, M.; Rahman, A. J. Appl. Phys. 1981, 52, 7182.
(18) Hess, B.; Bekker, H.; Berendsen, H. J. C.; Fraaije, J. G. E. M. J.
Comput. Chem. 1997, 18, 1463.
(19) van Gunsteren, W. F.; Billeter, S. R.; Eising, A. A.; Hünenberger,
P. H.; Krüger, P.; Mark, A. E.; Scott, W. R. P.; Tironi, I. G. Biomolecular
Simulation: The GROMOS96 Manual and User Guide; vdf Hochschulverlag
AG an der ETH Zürich, 1996.
(20) Berendsen, H. J. C.; Grigera, J. R.; Straatsma, T. P. J. Phys. Chem.
1987, 91, 6269.
(21) McDonald, I. R.; Rasaiah, J. C. Chem. Phys. Lett. 1975, 34, 382.
(22) Thiel, P. A.; Madey, T. E. Surf. Sci. Rep. 1987, 7, 211.
(23) Guidelli, R.; Schmickler, W. Electrochim. Acta 2000, 45, 2317.
(24) Henderson, M. A. Surf. Sci. Rep. 2002, 46, 1-308.
(25) Michot, L. J.; Viliéras, F.; François, M.; Bihannic, I.; Pelletier, M.;
Cases, J.-M. Geoscience 2002, 334, 611.
(26) Taylor, C. D.; Neurock, M. Curr. Opin. Solid State Mater. Sci.
2005, 9, 49.
Schravendijk et al.
(27) Verdaguer, A.; Sacha, G. M.; Bluhm, H.; Salmeron, M. Chem. ReV.
2006, 106, 1478.
(28) Shelley, J. C.; Patey, G. N.; Bérard, D. R.; Torrie, G. M. J. Chem.
Phys. 1997, 107, 2122.
(29) Shelley, J. C.; Bérard, D. R. ReV. Comput. Chem. 1998, 12, 137.
(30) Ghiringhelli, L.; Delle Site, L. In preparation.
(31) Jorgensen, W. L.; Tirado-Rives, J. J. Am. Chem. Soc. 1988, 110,
1657.
(32) The setup for the DFT calculation of this phenylalanine conforma-
tion is the same as that specified in ref 14, except that a 4 × 4 Ni(111)
surface was always used.
(33) Berendsen, H. J. C.; Postma, J. P. M.; van Gunsteren, W. F.;
Hermans, J. In Intermolecular Forces; Pullman, B., Ed.; D. Reidel
Publishing Company: Dordrecht, The Netherlands, 1981; pp 331-342.
(34) Jorgensen, W. L.; Chandrasekhar, J.; Madura, J. D.; Impey, R. W.;
Klein, M. L. J. Chem. Phys. 1983, 79, 926.
(35) Mahoney, M. W.; Jorgensen, W. L. J. Chem. Phys. 2000, 112, 8910.
(36) Guillot, B. J. Mol. Liq. 2002, 101, 219.
(37) Vega, C.; Sanz, E.; Abascal, J. L. F. J. Chem. Phys. 2005, 122,
114507.
(38) Hess, B.; van der Vegt, N. F. A. J. Phys. Chem. B 2006, 110, 17616.
(39) Shirts, M. R.; Pande, V. S. J. Chem. Phys. 2005, 122, 134508.
(40) Raschke, T. M.; Levitt, M. J. Phys. Chem. B 2004, 108, 13492.
(41) Schravendijk, P.; van der Vegt, N. F. A. J. Chem. Theory Comput.
2005, 1, 643.
(42) Cooper, T. G.; de Leeuw, N. H. Langmuir 2004, 20, 3984.
(43) Delle Site, L.; Sebastiani, D. Phys. ReV. B 2004, 70, 115401.
(44) Delle Site, L.; Alavi, A.; Abrams, C. F. Phys. ReV. B 2003, 67,
193406.
(45) Hess, B. J. Chem. Phys. 2002, 116, 209.