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Interaction Mechanisms and Interface Configuration of Cysteine

Adsorbed on Gold, Silver, and Copper Nanoparticles
Penélope Rodríguez-Zamora,* Cédric A. Cordero-Silis, Jorge Fabila, Jonathan Casildo Luque-Ceballos,
Fernando Buendía, Alejandro Heredia-Barbero, and Ignacio L. Garzón
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ABSTRACT: Cysteine-protected metal nanoparticles (NPs) have shown interesting

physicochemical properties of potential utility in biomedical applications and in the
understanding of protein folding. Herein, cysteine interaction with gold, silver, and
copper NPs is characterized by Raman spectroscopy and density functional theory
calculations to elucidate the molecular conformation and adsorption sites for each
metal. The experimental analysis of Raman spectra upon adsorption with respect to
free cysteine indicates that while the C−S bond and carboxyl group are similarly
affected by adsorption on the three metal NPs, the amino group is sterically
influenced by the electronegativity of each metal, causing a greater modification in the
case of gold NPs. A theoretical approach that takes into consideration intermolecular
interactions using two cysteine molecules is proposed using a S−metal−S interface
motif anchored to the metal surface. These interactions generate the stabilization of
an organo−metallic complex that combines gauche (PH) and anti (PC) rotameric
conformers of cysteine on the surface of all three metals. Similarities between the
calculated Raman spectra and experimental data confirm the thiol and carboxyl as adsorption groups for gold, silver, and copper NPs
and suggest the formation of monomeric “staple motifs” that have been found in the protecting monolayer of atomic-precise thiolate-
capped metal nanoclusters.

■ INTRODUCTION
In the last decades, cysteine has become a popular stabilization
agent for small metal nanoparticles (NPs), particularly in new
synthesis methodologies which are simpler, more biocompat-
ible, and more economic than their predecessors.1−5 Cysteine-
protected metal NPs (MetalCys NPs) have shown interesting
optical properties,1,6,7 water-solubility for environmental
applications,8,9 and bio-compatibility for biomedical applica-
tions,10−14 and they have been central subject for the study of
protein interactions with NPs as bioconjugates and protein
folding.10,15,16 The mechanisms of cysteine chemisorption on
the surface of metal NPs have been widely studied for the case
of gold, not so much for silver, and scarcely for copper NPs.
However, the abundance, chemical similarity, and economical
aspects make silver and copper NPs feasible and attractive
candidates for several applications.
The strong covalent bonds between the sulfur atom
belonging to cysteine’s thiol group, and these three metals
result in the formation of the Au−S, Ag−S, and Cu−S bonds,
respectively,17−19 which anchors the zwitterionic cysteine
ligand to the surface of such metal NPs, often also adsorbed
via its carboxylate group, as reported for the case of gold and
silver.11,20,21 Adsorption configuration and binding sites of
cysteine on gold NPs have been previously ascertained,20,22−25
paving the way for a better understanding of how the
intermolecular and the molecular−NP interactions determine
the electronic and geometric configuration of the system and
therefore its chiral activity.26 Copper and silver belong to the
same group as gold in the periodic table; thus, it is expected to
form similar core/shell geometries and ligand environments.27
However, there is theoretical and experimental evidence, which
demonstrates that silver and copper NPs have preferential
binding motifs and core geometries that differ from gold NPs
due to the different bonding nature and electronegativity
existing between the three metals.28
An experimental and theoretical comparison of the
adsorption behavior of cysteine on gold and silver NPs have
already been reported by means of surface-enhanced Raman
spectroscopy (SERS) and density functional theory (DFT)
studies,21 indicating that while on Au NPs, cysteine adsorbs via
its S atom and carboxyl and amino groups, on Ag NPs, it
adsorbs only via its carboxyl and amino groups since it tends to
form disulfide bonds. However, for this study, the silver NPs
Received: December 18, 2021
Revised: April 11, 2022
Published: April 21, 2022

© 2022 American Chemical Society https://doi.org/10.1021/acs.langmuir.1c03298

5418 Langmuir 2022, 38, 5418−5427
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are activated by coadsorption of chloride anions, which
positively charge the silver atoms, driving to the interaction
of the charged NPs with the deprotonated sections of the
cysteine molecules on one hand and causing the formation of
cystine on the other, therefore influencing the interface
configuration considerably. A previous theoretical study also
compared gold and silver thiol-protected NPs,29 and they
found that, upon molecular adsorption, atomic distortions are
induced on Au NPs while not on Ag NPs, which causes higher
molecular adsorption energies for Au NPs than that for Ag
NPs. Structural distortions and the specific molecular
adsorption sites and orientation result in chiral metal−thiolate
NPs. A comparison of this nature with copper NPs has not
been published to the best of our knowledge.
Although many methods have been proved successful for the
synthesis of stable cysteine-capped silver NPs,30−33 their exact
adsorption configuration and electrokinetic properties have not
been determined yet.11 Experimentally, it has been observed
that cysteine bound to Ag NP surfaces creates modified
interfaces with unique properties.9,10 Previous studies on the
thiolate−Ag(I) complexes suggested a possible coordination of
Ag(I) through S and a weak bonding through O, forming a
structure with hydrogen-bond interactions (N−H···OC).34
Other studies suggest that the amino and carboxyl groups of
cysteine are involved in mutual intermolecular interaction35 or
in interaction with the surface of Ag NPs in the case of non-
zwitterionic cysteine.9,10
In the case of cysteine-capped copper NPs, a composition of
Cu(0) and Cu(I),6,36,37 similar to Au NPs,5,26 has been
reported: core atoms forming Cu−Cu bonds, expected to have
oxidation state zero and atoms in the metal−organic
framework with Cu−ligand bonds to have oxidation state
+1,27 determining the whole atomic structure of the ligand-
protected NPs and therefore the adsorption configuration of
cysteine.
Raman spectroscopy is a useful analytical tool able to
provide detailed structural information of thiolate ligand
adsorption configuration and sites on metal NPs, yielding
vibrational signatures ascribed to the kinematics and conforma-
tional state of the ligand, the ligand−NP interface, and even
fingerprint features of the core metal atoms.38,39
Modifications to the main cysteine bonds upon adsorption
on the metal NP surface, including torsional motions and the
metal−S emerging bonds, are reflected in the Raman spectrum
of the metal−Cys (metal = Au, Ag, and Cu) sample, from
which the new ligand conformation can be interpreted, and
Raman effect differences depending on the interaction with
metals with different polarizabilities can be identified.17,39−41
The main objective of this work is to determine the
adsorption conformation of cysteine on Au, Ag, and Cu NPs.
Here, we report a systematic experimental−theoretical
approach to study the interface motifs upon adsorption of
cysteine on the three metal NPs. One aspect of novelty in the
present study is to point out the similarities and differences of
the adsorption conformation of cysteine on the three noble
metal NPs. For this purpose, we carried out the synthesis of
small Au, Ag, and Cu NPs (2−5 nm in diameter) by
microwave-assisted hydrolysis, induced the adsorption of
cysteine in each case, and afterward characterized each system
by Raman spectroscopy. In order to reach deeper insights into
the cysteine−metal interactions, theoretical calculations were
performed with Au, Ag, and Cu nanoclusters composed of 34
atoms, and their Raman spectra were calculated when two
5419
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cysteine molecules are adsorbed on their surface. Based on
both experimental and theoretical Raman spectra, we report
the formation of an organo−metallic complex of adsorbed
cysteines combining gauche (PH) and anti (PC) molecular
rotamers, mediated by the surface of gold, silver, and copper
NPs. Results also confirm the thiol and carboxyl groups as
adsorption agents for the three metals.
■ MATERIALS AND METHODS
Experimental Methods. Synthesis of Bare and Cysteine-
Protected Metal NPs. Tetrachloroauric acid (HAuCl4·3H2O,
≤99.9%), silver nitrate (AgNO3, 99.5%), and hydrated copper nitrate
(Cu(NO3)2·3H2O, 99.5%) were purchased from Sigma-Aldrich and
used without further purification. Gold (AuNPs), silver (AgNPs), and
copper NPs (CuNPs) were synthesized by microwave-assisted
hydrolysis according to a previous reported method with some
modifications.42 Nucleation of small NPs (∼2 nm) was induced using
a commercial Microwave System with a microwave frequency of 2.5
GHz. To prepare bare Au, Ag, and Cu NPs, 10 mL of a 2.5 mM
HAuCl4, AgNO3, and Cu(NO3)2 aqueous solution, respectively, were
placed in 15 mL falcon tubes, irradiated at 1000 W for 10 s and
cooled at room temperature.
L-Cysteine was purchased from Sigma-Aldrich and directly
dissolved in deionized water for a stock solution at a concentration
of 250 mM. Upon dissolution, the pH was 6, corresponding to the
zwitterionic species. In order to induce cysteine adsorption on Au, Ag,
and Cu NPs, a sample solution was prepared from the previously
described L-cysteine stock solution and each metal NP stock solution
for a final concentration of 150 and 0.25 mM, respectively. All sample
preparations were performed using ultrapure water and at room
temperature.
Sample Characterization. Transmission electron microscopy of
bare and cysteine-protected Au, Ag, and Cu NPs was performed with
a JEOL-ARM200F Cs-aberration-corrected electron microscope
operating at 80 kV through scanning transmission electron
microscopy (STEM) imaging with high angle annular dark field
detection. Samples of AuCys NPs, AgCys NPs, and CuCys NPs
described above were also characterized by Raman spectroscopy in
the liquid phase. Approximately, 50 μL of each sample was placed on
a magnesium fluoride window that performed as the liquid cell holder
and substrate.43 Raman spectra were collected with a DXR Raman
spectrometer (Thermo Fisher Scientific) system with the 532 nm line
of a Nd/YVO4 DPSS laser, using the 50× objective to focus it in the
sample for data acquisition. The exciting power at the sample was ca.
7 mW with typical exposure time of 12 s and at least 10 repetitions.
The scattered light collected was analyzed on a triplet spectrograph at
intervals of 1.0 cm−1 with an integration time of 1.5 s and spectral slit.
The system is equipped with a 900 lines/mm holographic grating and
a spot size of 0.7 mm slit. A cooled CCD detection system was used
to acquire Raman data, captured with a single exposure. All Raman
spectroscopy measurements were performed at 21 °C.
Computational Methods. Geometry optimization and Raman
calculations have been performed for a model consisting of a gold,
silver, and copper cluster with 34 atoms and C3 symmetry,44 with two
zwitterionic cysteine molecules adsorbed on the metal surface in all
possible rotameric configurations. This model is based on previous
results of systems consisting of thiolate-protected metal NPs,39,45,46
where a sulfur−metal−sulfur interaction occurs. The structure is
relaxed with no restrictions, and a frequency calculation of the
optimized system confirmed that we are located at a minimum point
on the potential energy surface (PES).
The introduction of two cysteines in the calculations catches the
interactions that could not be observed with one cysteine but avoids
the extra computational effort of calculating the system surrounded
completely by cysteine molecules. The formation of the staple-like
motif was induced by raising one metal atom of the cluster located
between the two cysteines and relaxing locally the new geometries.
Calculations for the lone cysteine were also performed, in order to
compare the changes in the molecule upon adsorption on each cluster
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Figure 1. STEM images of cysteine-protected Au (left), Ag (middle), and Cu NPs (right), including a high-resolution image of a representative NP
in each case and the corresponding histogram of size distribution.

surface. Frequency analysis has been performed for all the systems, further modifications as it has been pointed out be-
requesting the Raman intensities and wavenumbers to be compared fore.20,21,31,35
with the Raman experimental spectra. Negative frequencies were not Raman spectroscopy confirmed the adsorption of cysteine
found, confirming that the geometries are minima of the PES.
For all DFT calculations (optimization and frequencies), the PBE on Au, Ag, and Cu NPs through the sulfur atom (after breaking
functional was employed47 with the LANL2DZ48 basis set for the the S−H bond) by the disappearance of the thiol SH(str) mode
metal atoms (Au, Ag, and Cu), which has 19 valence electrons and (Figure 2b−d) with vibrational band at 2581 cm−1 (Figure 2a).
includes relativistic effects in the effective core potential. For the
remaining atoms (H, C, N, O, and S), the all-electron 6-31G(d,p)49
basis set was employed. All the calculations were performed using the
Gaussian 09 package,50 and for the visualization of the results, the
Gabedit 2.5.051 and Avogadro 1.1.1 were used.52 This level of theory
has been tested, providing excellent results in calculations of
structural, vibrational, electronic, optical, and chiroptical properties
of thiolate-protected small Au clusters.53−55
The assignment of the Raman peaks to a group of the molecule was
performed by means of the projection of the atomic displacements or
eigenvectors (Δrik) of each vibrational normal mode over the bonds
of the molecule (rij)
Δrik · rij
Proj =
||Δrik||||rij|| (1)
Only the eigenvectors (Δrik) greater than 0.1 Å are considered to
avoid false assignments due to the introduction of noise from the
calculation. An absolute value close to 1 means a displacement parallel
to the bond between the atoms i and j, being the positive value a
displacement that stretches the bond, while a negative value is related Figure 2. Normalized Raman spectra of (a) cysteine and cysteine-
with the compression of the bond. On the other hand, the values close protected (b) Au, (c) Ag, and (d) Cu NPs.
to zero correspond to displacements perpendicular to the bond. The
combination of these values allows us to distinguish the group
involved in each vibrational normal mode and the type of vibration Figure 2 shows the overall differences between Raman
(Tables S2−S5).

■
RESULTS AND DISCUSSION
Experimental Raman Spectra of Metal−Cys NPs.
Presence of Au, Ag, and Cu NPs at a high concentration in
colloidal solution obtained by hydrolysis assisted by micro-
waves without the incorporation of stabilizing ligands was
confirmed by STEM (Figure S1). Samples of cysteine
adsorbed on Au, Ag, and Cu NPs (AuCys NPs, AgCys NPs,
and CuCys NPs) were first examined by STEM, demonstrating
high dispersion with no agglomeration and an average
diameter of 2−5 nm (Figure 1).
The absence of reduction agents in this synthesis technique
allows us to study the adsorption mechanisms and interface
configuration of cysteine on Au, Ag, and Cu NPs without
5420
spectra corresponding to free cysteine (Figure 2a) and cysteine
upon adsorption on Au, Ag, and Cu NPs (Figure 2b−d). An
analysis of the effect of each metal can be performed by the
wavenumber region, as it is detailed below, including Raman
shifts of key vibrational bands corresponding to the metal−S
interaction and intramolecular bonds including the C−S bond
and vibrations of the amino and carboxyl functional groups.
Our observations suggest that the thiol and carboxyl groups are
involved in the adsorption process of cysteine on all three
metal NPs, displaying similar Raman tendencies for all three
metals, whereas the amino group shows differentiated behavior
as function of the metal NP and seems to be sterically modified
by the proximity to the metal surfaces.
Also, experimental evidence points to more than one
molecular configuration of adsorbed cysteines on the surface
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Figure 3. Normalized Raman spectra of free cysteine (blue) and cysteine adsorbed on Au (amber), Ag (gray), and Cu NPs (brown) in regions
from (a) 400−600 cm−1, including features corresponding to the disulfide bond between neighboring cysteines for the case of AgCys and (b) 100−
400 cm−1, including features corresponding to the metal−S bonds for all three metals.

Figure 4. Normalized Raman shifts of cysteine experimental spectrum upon adsorption on metal NPs by the region. Raman spectra corresponding
to cysteine adsorption on Au NPs (amber, top panels); Ag NPs (gray, middle panels); and Cu NPs (brown, bottom panels) compared to free
cysteine Raman spectrum (blue) in all cases.

of the metal NP, combining gauche (PH) and anti (PC)
rotameric conformers.
200−400 cm−1 (Metal−S Bond). The metal−S (Cys)
frequency is a direct indicator of metal−ligand bond formation
and, hence, Au−, Ag−, and Cu−ligand coordination geometry.
Raman spectroscopy of gold clusters with thiolate ligands
provides fingerprint vibrational features below 200 cm−1,
involving vibrational modes of metal atoms in the cluster
core,39 while vibrational signatures of outer metal−ligand
staple motifs have been identified between 200 and 500
cm−1.38 Metal−S vibrational modes have been identified below
400 cm−1 for cysteine adsorbed on Au and Ag NPs and
between 350 and 450 cm−1 for Cu NPs.8,9,17,22,31,56−58
Within this spectral range, for AuCys NPs, we identified a
weak Raman band at 255 cm−1 that could be associated with
tangential stretching Au−S vibrations of SR-Au-SR staples;38 a
5421
strong band at 300 cm−1, assigned as a radial stretching Au−S
vibration, involving perpendicular movements of the thiolate
against the NP surface38,59 (Figure 3b).
Raman spectra for AgCys NPs and CuCys NPs show weak
bands at similar frequencies. AgCys NPs display weak bands at
198 and 214 cm−1 (Figure 3b), in partial agreement with those
previously reported at 207 and 211 cm−1;9 at 267 cm−1;21 at
227, 250, and 260 cm−131 for Ag−S and Ag−N stretching
vibrations; and at 312 cm−1. In the case of CuCys NPs, the
spectrum shows bands at 251, 310, and 367 cm−1(Figure 3b),
which are at lower frequencies than those previously reported
as symmetric vibration of Cu−S at ∼404 cm−1,8 but in
agreement with precedent findings that report a Cu−S
stretching band at 370 cm−1,60 and approximately in the
same range that includes observed bands at 420, 390, and 340
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cm −1 depending on the ligand−Cu atom interaction
configuration.17
By comparing the three metals, it is possible to observe that
metal−S bands are better defined in the case of Au NPs,
followed by Cu NPs and, finally, Ag NPs display the weakest
and least defined bands of all. In all cases, theoretical findings
demonstrate metal−sulfur vibrations at frequencies in close
agreement with the previously mentioned bands, as described
in Section 3.2.
400−600 cm−1 (S−S Bond). A feature to notice is the
emergence of a double band at 500 cm−1 in the case of AgCys
NPs and a sharp band at 480 cm−1 in the case of CuCys NPs,
where free cysteine and AuCys NPs do not present any
relevant peaks (Figure 3a). Bands between 512 and 520 cm−1
have been previously identified as stretching vibrations
belonging to the S−S bond formed in cystine10,15,21,61 that
do not exclude molecular interaction with the metal surface
through the thiol group, argumenting the S−S bond being
tilted against the NP surface and interacting through electron
lone pairs without sulfide bridge cleavage.10 More recent
results demonstrate that the S−S band vanishes after
prolonged sample incubation,15 an effect that is attributed to
kinetic and thermodynamic reasons. The disulfide binding to
Ag NP is both kinetically and thermodynamically more
unfavorable than that for carboxylate, the S−S cleavage only
occurs when the carboxyl groups in cystine (Cyt) are fully
reacted with silver ions derived from Ag NPs.15 It can be
therefore suggested that cysteine adsorption on Ag NPs
propitiates the formation of disulfide bonds, forming cystine
(in agreement with Jing and Fang21), at least during the first
stages of the complex formation, while this phenomenon does
not occur in the case of Au NPs and it is uncertain, given the
lower wavenumber of the band in question, in the case of Cu
NPs.
600−800 cm−1 (C−S Bond). The CβS stretching band,
found between 600 and 800 cm−1, depending on cysteine’s
configuration, is sensitive to the torsion angle NCαCβS and
molecule polarizability,8,10,20,22 therefore providing informa-
tion about the rotational configuration of the molecule upon
adsorption on metal NPs.11,21,62
The CβS stretching band shows similar behavior for all three
metal NPs; it redshifts with respect to the CβS band of the free
ligand (at 690 cm−1) to 662, 677, and 668 cm−1 for adsorption
on Au, Ag, and Cu NPs, respectively (Figure 4g−i), in close
agreement with previous findings reported for NPs of each
metal,8,9,11,21,22,35,59,60,63 and confirming a structural modifica-
tion of the ligand configuration taking place during adsorption.
The analysis of this band also indicates that cysteine adsorbs
through its thiol group on all three metal NPs, with Au NPs
enabling the strongest interaction (largest redshift),62,64,65
followed by Cu NPs and finally Ag NPs.
For all three metal NPs, it is possible to observe band
multiplicity for the CβS stretching vibration (Figure 4g−i),
which can be interpreted as more than one rotational
conformer of cysteine adsorbed on the metal surfaces.11,59,65
The rotameric conformation determines what atoms are in
proximity to the metal surface and therefore the molecular
adsorption sites. For cysteine, there are three possible isomeric
rotational conformers, or rotamers: PH (the hydrogen atom in
antiposition with respect to the sulfur atom in a gauche
orientation of the NCαCβS moiety); PC (the carboxyl group in
antiposition with respect to the sulfur atom); and PN (the
amino group in antiposition with respect to the sulfur atom in
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a trans arrangement of the N and S atoms linked by the two
carbon atoms) (Figure 5), which are arbitrated by the
Figure 5. Cysteine possible rotameric conformers. (a) PN (anti(I)
orientation): the amino group in antiposition with respect to the
sulfur atom in a trans arrangement of the N and S atoms linked by the
two carbon atoms; (b) PC (anti(II) orientation): the carboxyl group
in antiposition with respect to the sulfur atom; and (c) PH (gauche
orientation): the hydrogen atom in antiposition with respect to the
sulfur atom.
orientations of the CαCβS group. Previous studies indicate
that free cysteine in solution tends to adopt a P N
conformation,62,65,66 while different combinations of the
three rotamers, PN, PC, and PH, have been suggested to
stabilize upon adsorption on Au and Ag NPs with no apparent
consensus.10,22,31,65 The PN rotamer displays CβS bands at
higher wavenumbers than PH and PC,22,59 based on which we
can infer that this rotamer might not be present when
adsorbing on either of the metal NPs. On the other hand,
differentiating between PC and PH cysteine rotamers only from
Raman bands is rather difficult since both orientations result in
similar vibrational peaks in this spectral region,22 enabling the
possibility of a mixed molecular configuration combining both
rotamers PCPH.
800−1200 cm−1 (Amino and CN Bands). The free cysteine
Raman region between 800 and 1000 cm−1 includes bands
involving the nitrogen atom that have been assigned as an
NH3+ rocking vibration at 878 cm−122 and a HCαN bending
vibration at 940 cm−1.65,67 Upon adsorption, the above bands
shift, respectively, to 906 and 953 cm−1 for Au NPs, 870 and
938 cm−1 for Ag NPs, and 877 and 970 cm−1 for Cu NPs
(Figure 4d−f).
In this case, the cysteine amino group behaves differently
depending on the metal NP: while for Au NPs, there is a
blueshift of the cysteine amino group vibrations that can be
explained by a decrement of the NCαCβS dihedral angle
magnitude upon adsorption when considering a transition
from PN to PC (and also to PH) rotational conformation (Table
S1),20 when cysteine is adsorbed on Ag and Cu NPs, there is
no Raman shift greater than the associated error. This result
suggests that although adsorption on Au NPs infringes a more
significant steric modification upon cysteine’s amino group,
possibly due to its higher electronegativity,23 the NH3+
functional group does not adsorb directly on the metal surface
of any of the three different NPs.
Finally, it is worth noticing that the mentioned HCαN band
blueshifts for the three metals (Figure 4d−f) and that other
CαN bands, located between 1000 and 1150 cm−1,10,11,22,62,65
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are recovered (compared to a poorly resolved region for the
free cysteine spectrum)20 upon adsorption on the three metals,
principally on Au NPs, followed by Cu NPs and finally Ag NPs
(Figure 2). An interpretation for such behavior will be further
discussed based on theoretical results in Section 3.2.
1200−1600 cm−1 (Carboxyl Bands). Some of the main
carboxyl symmetric stretching bands of free cysteine are
located in the spectrum region between 1350 and 1450
cm−1.65,67−69 Upon adsorption, CγOO− bands detected at
1356 and 1406 cm−1 for the free molecule shift, respectively,
toward lower frequencies at 1334 and 1385 cm−1 for Au NPs,
1356 and 1386 cm−1 for Ag NPs, and 1338 and 1386 cm−1 for
Cu NPs (Figure 4a−c).
In the case of AuCys NPs, there is agreement among
different research groups that the molecule uses its carboxyl
mode to interact with the NP surface.20,21,59,65 SERS
enhancement of COO− symmetric stretching observed at
1391 cm−1 along with CH2 rocking vibration and bending
vibration at 1295 and 1337 cm−1, which are short of p or lone-
paired electrons, suggest a charge transfer from the p electron-
rich CγOO− moiety of the adsorbate to the gold surface,
confirming a chemical attachment of the carboxyl group to the
gold NP surface.21
In contrast, for AgCys NPs, while most reports, based on
SERS, FTIR, and Raman experimental results, indicate the
formation of an O−Ag bond,11,21,31,34,62 others claim that
cysteine-protected Ag NPs have the carboxyl group exposed
outside due to electrostatic repulsion between the negatively
charged CγOO−−CγOO− groups of adjacent molecules.9 In
more recent studies,15 it has been suggested that despite
cysteine thiolate interaction with Ag NPs is thermodynamically
more favorable than the interaction of its carboxyl group, it
might be kinetically slower, therefore forming a Ag−carboxyl
complex which subsequently converts to a more stable Ag−
thiolate complex.
Finally, our results for cysteine adsorbed on Cu NPs are in
agreement with previous FTIR findings that confirm a
cysteine’s anchor through Cu−O bonding.70
This generalized behavior observed for all three metals
indicates that the chemical interaction of the three metal NPs
influences equivalently the configuration of this functional
group. The tendency of the carboxyl group vibrations to
redshift demonstrates an overall weakening of the CγOO−
bonds, which can be interpreted as a direct interaction between
this group and the metal surface.
Adsorbed Cysteine Configuration and Theoretical
Raman Spectra. Previous studies of cysteine adsorption on
gold NPs20,22 demonstrate, using models with one cysteine
adsorbed on the NP surface, that this interaction is mainly
mediated by the S−Au bond followed by the O−Au bond and
highly dependent on the stabilized rotamer due to steric
impediments. However, an improved approach is required to
catch adsorption interactions, that could not be observed with
the mentioned models, as the intermolecular interactions and
the formation of interface motifs that generate the oxidation of
a metal atom and a change in the coordination number of the
sulphur group, inducing modifications in the geometric
structure of the adsorbed molecule.
In order to ascertain the nature of such adsorption
mechanisms, we propose a theoretical model consisting of
two cysteine molecules adsorbed on gold, silver, and copper
clusters with 34 atoms (Metal34Cys2) (Figure 6).
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Figure 6. Theoretical models for the adsorption configuration of (a)
Au34Cys2, (b) Ag34Cys2, and (c) Cu34Cys2, with molecular rotameric
conformation PCPH. The bottom panels show a lateral view
emphasizing the intermolecular bond between the oxygen of the
carboxyl group of one cysteine molecule with the hydrogen of the
amino group of the neighbor cysteine for Au (left), Ag (middle), and
Cu (right).
Compared to models with one cysteine, the main differences
when the second molecule is introduced are two: first, the
formation of a previously proposed interface motif with
arrangement S−metal−S26 for the three metals that resembles
the staple motif known for gold NPs. This interface motif is
anchored to the metal surface mainly by the sulfur from the
thiol group, increasing the coordination number of sulphur
which in turn decreases the strength of the CβS bond of the
molecule, and by one of the oxygens of the carboxyl group.
Second, the intermolecular forces are reflected in the
formation of hydrogen bonds between adjacent adsorbed
cysteines. These interactions generate molecular steric
modifications that lead to the stabilization of a particular
arrangement of cysteine rotamers on the NP surface
corresponding to P C P H for all three metals. In this
configuration, an intermolecular hydrogen bond is established
between one of the oxygens from the carboxyl group of one
cysteine and one hydrogen atom from the amino group of the
second molecule (Figure 6), building a supra-structure for the
adsorbed cysteines. The formation of coordination complexes
of this nature mediated by metal clusters as the substrate has
been previously suggested for gold23 and silver34 NPs by NMR
and FTIR studies, respectively, and it could be a plausible
explanation for the experimental observations regarding the
CαN Raman bands, as described in Section 3.1.4. On one hand,
the interconnecting H bonds cause the weakening of the NH3+
and thus a strengthening of the HCαN bond, which is reflected
on a blueshift of the CαN band at 940 cm−1 (Figure 4d−f). On
the other hand, the cysteine coordination complex formed on
the surface of all three metal NPs reconstitutes the stability of a
crystal environment rich in H bonds that is lost in the liquid
phase20 and which is reflected on the recovery of CαN bands
between 1000 and 1150 cm−1 (Figure 2), particularly in the
case of AuCys NPs.
For this model, the PCPH rotamer is the only configuration
that enables intermolecular H bonds between carboxyl and
amino groups of adjacent cysteines and, simultaneously,
adsorption to the metal surface through an oxygen atom
(Figure S2). Moreover, PCPH is the molecular configuration
that generates the Raman spectra that better resembles the
experimental results for all three metals, compared with the
https://doi.org/10.1021/acs.langmuir.1c03298
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other combinations in the bi-molecular models (Metal34Cys2
PCPC and PHPH) and the equivalent models with only one
cysteine (Metal34Cys PC and PH) (Figures 7, S3−S6). This
Figure 7. Comparison of the calculated Raman spectra for (a)
Au34Cys2 (amber); (b) Ag34Cys2 (gray); and (c) Cu34Cys2 (brown)
with experimental Raman spectra (black) for cysteine-protected gold,
silver, and copper NPs, respectively.
outcome is in line with an steric argument pointing to PC
instead of PH (rotamer of minimum energy in the case of one
adsorbed cysteine), suggested by previous results in the case of
gold NPs.20,22
The Raman spectra corresponding to cysteine functional
groups upon adsorption on gold, silver, and copper clusters
were theoretically calculated in the region from 200 to 1600
cm−1, where the effect of the different metals can be observed
(Figure 7).
In the region from 200 to 400 cm−1, we found the
frequencies associated with the metal−S vibration. For the
AuCys case, the peak at 236.15 cm−1 is correlated with metal−
Figure 8. Raman shifts of cysteine theoretical spectrum upon adsorption on metal NPs by the region. Raman spectra corresponding to cysteine
adsorption on Au NPs (amber, top panels); Ag NPs (gray, middle panels); and Cu NPs (brown, bottom panels) compared to free cysteine Raman
spectrum (blue) in all cases.
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sulfur vibrations corresponding to the Au(0), and the bands at
308.36 and 344.32 cm−1 correspond to Au(I)−S. In the case of
AgCys, at 268.32 cm−1, Ag−S symmetrical stretching appears,
and at 314.44 cm−1, there is the anti-symmetrical band. For the
CuCys case, we observed bands at 265.44 and 301.36 cm−1,
where Cu(0) and Cu(I) are involved. These bands are in
agreement with our experimental spectra, as shown in Figure
3b.
Of particular interest is the C−S bond, which presents a
redshift upon adsorption on all three metal NPs with respect to
free cysteine, in agreement with the experimental results
(Figure 8g−i). This shift is associated with the increase in the
C−S bond length (Table S1) due to its weakening, which is in
turn provoked by the back donor effect from the electrons of
the NP toward the empty orbitals of the C−S group. Such an
effect is related to the S−metal(I) interaction, and it has been
proposed as a fingerprint of our interface motif. The large
redshift for cysteine-capped Au NPs has been earlier explained
by electron donation from the sulfur atom to the gold atom,21
which also explains why this effect is more noticeable on gold
than that in silver and copper, given its higher electronegativity
(the Pauling electronegativity values for the different species
are 2.54 for Au, 1.93 for Ag, and 1.90 for Cu). This result is
consistent with the stronger and better defined Au−S bands
compared to Ag−S and Cu−S in the 200−400 cm−1 spectral
region (Figure 3b).
Given that the CβS bond depends on the interaction
between the carboxyl group with the SH group and therefore
on the orientation of both functional groups,10 the described
coincidences found for the three metals reveal that the rotamer
adopted by cysteine is similar in the three cases. The redshift
for all metal NPs suggests a modification of the torsion angle
NCαCβS from an obtuse negative angle to an acute positive
angle.20,63 This is in agreement with the dihedral angles
corresponding to the free ligand (PN rotamer Figure 5a) and
the ones corresponding to adsorbed cysteine (PC or PH Figure
5b,c), respectively (Table S1).20,63,65 This geometrical result
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Langmuir 2022, 38, 5418−5427
Langmuir pubs.acs.org/Langmuir
confirms a major modification for the torsion angle in the case
of cysteine adsorption on Au NPs.
In terms of adsorption sites, the interaction of cysteine on
Ag and Cu NPs is also mediated mainly by the S−metal
interaction, in accordance with the previous results due to the
nucleophilic character of the groups.26,71 However, a Bader
analysis reveals that the COO− group binds to the metal
surface for Au, Ag, and Cu NPs via a free pair electron and
brings with that a small charge transfer toward the NP. This
interaction also generates a back donor charge transfer from
the NP toward the molecule that is reflected in the increase in
one of the CO bond lengths (Table S1), observed as a redshift
of the corresponding Raman bands of the three metals (Figure
8a−c), in agreement with the experimental results (Figure 4a−
c).
Once the molecule is adsorbed to the surface of the NP, the
wavelength of the symmetrical and anti-symmetrical stretching
modes of COO− change by the dative bond formed between
one oxygen atom and the metal NP. This generates the
weakening of the C−O bond that is bonded with the metal NP
and the strengthening of the other C−O bond to a double
bond (Figure 8a−c). Charge analysis also suggests a positive
charge in the three metal atoms of the interface motif, being
the Cu atoms the most positive, followed by Ag and Au atoms
in that order. This is in accordance with the experimental
results that have shown the oxidation state of the staple motif
as +1.72−74
The values of the bond lengths for the different systems can
be observed in Table S1. These results demonstrate, along with
the experimental evidence, that simultaneously to its
intermolecular bridging role, cysteine’s carboxyl group also
performs as a second adsorption site for gold, silver, and
copper through its second oxygen atom.
On the other hand, the theoretical Raman spectra show
blueshifts for the NH3+ at 884 cm−1, larger for AuCys NPs,
followed by AgCys NPs, and finally by CuCys NPs (Figure
8d−f), which is in partial agreement with our experimental
results that display a blueshift of the band at 878 cm−1 only for
the case of AuCys NPs (Figure 4d−f). Both results can be
likely due to a change in the molecular dipole moment when
cysteine binds to the metal surface,23 being the greater shift
associated to higher electronegativity, which corresponds
precisely to gold.
■
CONCLUSIONS
Experimental and theoretical studies of the interaction of
cysteine with gold, silver, and copper NPs through the analysis
of Raman spectroscopy reveal that each metal modifies the
Raman spectrum of the adsorbed molecule in a characteristic
manner, displaying fingerprint features corresponding to the
metal−S and C−S bonds, as well as to the carboxyl and amino
functional groups, determined by the nature of each metal and
its interaction with cysteine. However, the tendencies of the
abovementioned relevant molecular groups indicate that the
adsorption mechanisms and the NP−molecule interface
configuration are similar for the three metal NPs with some
variations, particularly for the amino group, mainly due to the
different electronegativities of each metal.
The rotameric conformers of cysteine that stabilize on the
surface of Au, Ag, and Cu NPs are PC (the carboxyl group in
antiposition with respect to the sulfur atom) and PH (the
hydrogen atom in antiposition with respect to the sulfur atom
in a gauche orientation of the NCαCβS moiety), with sulfur
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Article
and carboxyl group as adsorption agents. This interaction is
restricted by steric conditions determined by the intermo-
lecular interactions between cysteine ligands forming hydrogen
bonds. The experimental and theoretical evidence of such
intermolecular interactions suggests the formation of an
organo−metallic complex of adsorbed cysteines in a PCPH
array, induced and mediated by the surface of gold, silver, and
copper NPs.
■
*
ASSOCIATED CONTENT
sı Supporting Information
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/acs.langmuir.1c03298.
STEM images of metal NPs; computational Metal34Cys2
models with cysteine molecules in PCPH, PHPH, and
PCPC rotameric configurations; comparison of exper-
imental and theoretical Raman spectra for PC, PCPC, PH,
and PHPH rotameric adsorption configurations for all
three metal NPs; bond distances and angles of cysteine
in the gas phase and the two cysteine molecules of
Metal34Cys2 in the PCPH configuration; wavelength and
group involved in vibrational normal modes accom-
panied by the norm of the eigenvectors; and the
projection of the eigenvectors over the bond vectors
(PDF)
■
AUTHOR INFORMATION
Corresponding Author
Penélope Rodríguez-Zamora − Instituto de Ciencias
Nucleares, Universidad Nacional Autónoma de México,
Mexico City 04510, Mexico; orcid.org/0000-0002-0963-
7046; Email: penelope.rodriguez@
correo.nucleares.unam.mx
Authors
Cédric A. Cordero-Silis − Instituto de Física, Universidad
Nacional Autónoma de México, Mexico City 04510, Mexico
Jorge Fabila − Instituto de Física, Universidad Nacional
Autónoma de México, Mexico City 04510, Mexico
Jonathan Casildo Luque-Ceballos − Instituto de Física,
Universidad Nacional Autónoma de México, Mexico City
04510, Mexico
Fernando Buendía − Instituto de Física, Universidad Nacional
Autónoma de México, Mexico City 04510, Mexico;
Department of Chemical and Biomolecular Engineering
Faculty of Engineering, National University of Singapore,
Singapore 119260, Singapore
Alejandro Heredia-Barbero − Instituto de Ciencias Nucleares,
Universidad Nacional Autónoma de México, Mexico City
04510, Mexico
Ignacio L. Garzón − Instituto de Física, Universidad Nacional
Autónoma de México, Mexico City 04510, Mexico;
orcid.org/0000-0002-4461-0228
Complete contact information is available at:
https://pubs.acs.org/10.1021/acs.langmuir.1c03298
Notes
The authors declare no competing financial interest.
■
ACKNOWLEDGMENTS
We would like to thank Cristina Zorrilla for technical support
for acquisition of Raman spectra. Also, we thank Josué Romero
https://doi.org/10.1021/acs.langmuir.1c03298
Langmuir 2022, 38, 5418−5427
Langmuir pubs.acs.org/Langmuir
for technical support for acquisition of STEM images.
Calculations were performed at the DGTIC-UNAM Super-
computing Center under Projects LANCAD-UNAM-DGTIC-
049 and LANCAD-UNAM-DGTIC-307. This work was
supported by DGAPA-UNAM PAPIIT under Project
IN106021 and CONACyT-México under Project 285821.
P.R.-Z. thanks CONACyT-México for the financial support
through a postdoctoral fellowship. F.B. and J.C.L.-C. acknowl-
edge support from DGAPA-UNAM through a postdoctoral
fellowship.
■
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https://doi.org/10.1021/acs.langmuir.1c03298
Langmuir 2022, 38, 5418−5427