Neopterin interactions with magic atom number coinage metal nanoclusters: A theoretical study

Andrey A. Buglak

doi:10.1515/pteridines-2025-0051

Article Open Access

Neopterin interactions with magic atom number coinage metal nanoclusters: A theoretical study

Andrey A. Buglak

Published/Copyright: June 18, 2025

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From the journal Pteridines Volume 36 Issue 1

Abstract

Metal nanoclusters (NCs) are novel materials with low cytotoxicity, high chemical stability, intense luminescence, etc. These characteristics are in great demand during biomarker detection and bioimaging. These properties of metal NCs are exploited by colorimetric, luminescent, and Raman tiny sensors. Neopterin (Nep) is used in medicine as a biomarker of inflammation and immune system activation, cancer, COVID-19, etc. The clusters of Au, Ag, and Cu with magic atom numbers m* equal to 2 and 10 were studied. Gibbs energy of complexation (E _b) has been established using density functional theory (DFT). The highest E _b was determined for the complexes of Au 2 + and Cu 2 + in an alkaline aqueous solution. As a rule, clusters change their symmetry upon the interaction with Nep; their physicochemical properties are also changed. The detection of Nep with Au and Cu NCs seems to be prospective using Raman detection. In particular, Raman detection of Nep should be done using Cu₉ NC, which interacts with all three Nep functional groups (pyrazine, pyrimidine, and side substituent) and causes significant chemical enhancement and shift of the Raman signal. The usage of coinage metal clusters and nanoparticles is expected for precise Nep detection in the near future.

Keywords: neopterin; metal nanoclusters; density functional theory; SERS; metal–ligand interactions

1 Introduction

Nanoclusters (NCs) of coinage metals are specific functional nanoobjects. They are largely exploited in multiple studies and applied technologies due to their unique physicochemical characteristics. These characteristics lead to the efficient production of signals when interplaying with bio-analytes [1].

Coinage metal clusters are exploited nowadays in biocatalysis, diagnostics, bioimaging, and biosensors due to their chemical stability, high biocompatibility, sensitivity to the molecular environment, low photobleaching, and tunable optical properties [2,3]. The characteristics of gold (Au) NCs are exceptionally unique; for this reason, they are frequently used in nanotechnology as compared to other metals and non-metal materials [4]. Silver (Ag) clusters are significant mostly because of their intense luminescence [5]. Copper (Cu) NCs have several advantages over Au and Ag clusters; they are high yield, raw abundance, low cost, and presence as a trace element in biosystems [6].

Coinage metal NCs can be obtained using DNA templates [7,8] and protein matrices [9], and their physicochemical properties and photophysics are intensively studied [10]. Metal clusters are used in nanosensor fabrication because of their tunable luminescence and efficiency in the detection of various substances [11,12], including organic molecules, ions, etc.

The metal NCs, which follow conventional magic atom numbers (2, 10, 18, 36, 54, and 86), possess the most attractive properties. The “superatom” concept explaining the emergence of magic atom numbers was developed in 2008 [13]. This concept says that the metal core is a “superatom” stabilized when its amount of electrons (e⁻) and e⁻-accepting groups conditions specific magic numbers. The equation for a magic number m* is as follows:

(1) m * = N Me − A − q ,

where N _Me is the amount of metal atoms, which is also the number of unpaired electrons, A is the amount of e⁻-accepting groups, and q is the charge of the cluster [14]. The e⁻-accepting groups may be various organic ligands including pterins.

Unconjugated pterins (Ptrs) are low-molecular-weight organic compounds with a natural origin; in living species, reduced pterins are important coenzymes. Their decay products, oxidized pterins, can serve as biochemical markers of mechanical trauma [15], oxidative stress [16], inflammation [17], gastrointestinal diseases [18], cancer [19], SARS-CoV-2 [20,21], etc. High-performance liquid chromatography and capillary electrophoresis are often used to detect pterins in biological fluids [22,23]. However, new techniques of pterin detection with improved precision, sensitivity, and cost-effectiveness are also being developed, for example, Raman spectroscopy with adsorption of carboxypterin on carbon nanopillars coated with Au [24]. Ag colloid can be used for the Raman detection of xanthopterin, isoxanthopterin, and 7,8-dihydrobiopterin [25].

Neopterin (Nep) is a degradation product of 7,8-dihydroneopterin (H₂Nep), which is a strong antioxidant produced by macrophages [26]. Serum and urinary Nep levels are determined by the macrophage activity [17]. Urinary Nep and total Nep (Nep plus H₂Nep) are biomarkers of oxidative stress [16] and cancer: it is established that preactivation of cell-mediated immunity is related to poor prognosis in cancer-affected organisms, as well as human immunodeficiency virus infected patients [27]. Monocytes and macrophages make Nep when stimulated by interferon-gamma released by T cells [28]. As a whole, Nep levels can be a sign of various diseases and pathologies, including atherosclerosis, arthritis, and severe cardiovascular diseases [29,30].

Vargas and Martínez studied Cu, Ag, and Au complexes with pterins and determined that metal anions, as well as ultra-small metal clusters, form non-conventional H-bonds with pterins, their dimers, and tetramers [31]. We have already simulated the interactions of Ag and Au clusters with pterin using density functional theory (DFT) [32,33]. We established that at alkaline pH > 8, the Raman spectrum of singly deprotonated Ptr⁻¹ undergoes dramatic changes upon the addition of Ag. Moreover, triatomic clusters of both Ag ( Ag 3 2+ ) and Au ( Au 3 2+ ) seem to be the most effective tools for Ptr detection with Raman spectroscopy. Moreover, coinage metals (mostly Au) are usually exploited in surface-enhanced Raman scattering (SERS) [34].

The detection of Nep in serum, urine, and cerebrospinal can be performed cost-effectively using coinage metal NCs. Nep–Me NC complexes can be quantitively determined with UV–vis, luminescent, infrared, and SERS spectra. Therefore, quantum-chemical simulations for Nep–Me NC complexes are necessary to establish the potential benefits of quantitative determination of Nep in biological fluids.

The aim of the study was to establish the interactions between coinage metal ultra-small NCs with magic atom numbers m* = 2, 10, and Nep. First, the binding energies to establish the most stable complexes were found. Second, the nature of metal–organic bonds was determined using quantum-topological analysis. Third, UV–vis and Raman spectra of the complexes were obtained to find the systems with significant potential for experimental detection of Nep.

2 Materials and methods

Geometry optimization and binding energy evaluation in Orca 5.0.2 [35] have been done using PBE functional [36]. Dispersion corrections were made with the Grimme method (D3) [37]. The 6–31 G(d,p) basis set was used along with the LANLTZ pseudopotential for the electrons of Au, Ag, and Cu since this method showed good results for metal complexes of DNA bases [38]. The CPCM polarizable continuum model has been used to take the influence of H₂O into account [39]. The geometries of Nep were treated by putting metal atoms near the atoms of pterin with e⁻ lone pairs: nitrogen and oxygen. Thus, the complexation reaction between Nep and metal NC looked as follows:

(2) Nep + Me m q ⟶ Nep − Me m q .

The binding energy between Nep and metal NCs (E _b) was established as follows: E _b = E _Nep + E _Me – E _Nep–Me. The calculation has been done for both the protonated form Nep⁰ and the deprotonated Nep⁻¹ (pK _a = 8 [40]).

The simulations of UV–vis and Raman spectra for the most energetically favorable complexes have been done. The absorption spectra were obtained using the time-dependent density functional theory, in particular, M062X functional [41], along with the def2-TZVP basis set [42]. This functional was shown to be accurate enough when simulating the spectra of the complexes for nucleobases bound to transition metals [43]. Finally, the Raman spectra were determined with B3LYP-D3/def2-TZVP. B3LYP shows sufficient results when compared to the experimental Raman spectra [44,45].

The natural bond orbital (NBO) analysis has been performed with B3LYP in Gaussian 16 [46]. The E ⁽²⁾ stabilization energy of the i → j ground state transitions has been obtained in accordance with the following equation:

(3) E ( 2 ) = − 2 ⟨ i ∨ F ˆ ∨ j ⟩ 2 e j − e i ,

where e i and e j are orbital energies for each donor NBO orbital i and acceptor orbital j, whereas F ˆ is the Fock operator.

Equation (4) is used to quantify the amount of charge transferred between e i and e j orbitals:

(4) q CT = 2 ⟨ i ∨ F ˆ ∨ j ⟩ e j − e i 2 .

The NBO and Quantum theory “Atoms-in-Molecules” (QTAIM) analysis have been performed previously to investigate Ag and Au NC complexes of pterin with a similar methodology [32,33].

3 Results and discussion

3.1 Geometry of the naked clusters

Structure and Gibbs free energies of individual metal atoms and isolated clusters ( Me 1 0 , Me 2 1 + , Me 2 0 , Me 3 1 + , Me 9 0 , Me 10 1 + , Me 10 0 , and Me 11 1 + ), which form magic number m* = 2 and 10 complexes with Nep⁰ and Nep⁻¹, have been established. The most stable of them are shown in Figure 1.

Figure 1

Geometry of isolated metal clusters, according to the PBE-D3/def2-TZVP method.

For the cationic triatomic clusters, interatomic distances equal to 2.63, 2.68, and 2.36 Å have been established for Au 3 + , Ag 3 + , and Cu 3 + , respectively. Each cluster is non-linear and forms an equilateral triangle, which is in agreement with previous studies [32,33,47].

Naked Au₉ is a planar 2D cluster with a C_2v symmetry point group. Ag₉ and Cu₉ possess C_s and C_2v symmetry, respectively, yet with a non-planar 3D geometry (Figure 1). This is in agreement with the latest research on Ag and Cu clusters [48,49]. Cartesian coordinates of the naked clusters are presented in Supplementary Materials.

The Au₁₀ cluster is planar; however, it possesses a D_3h symmetry, which is in agreement with previous research [50]. Ag₁₀ and Cu₁₀ are D_2d geometries, which does not contradict the literature data [51,52]. Upon detachment of an electron, D_2d symmetry does not change, forming D_2d Au 10 + and Cu 10 + clusters, which has already been reported for Ag [53]. However, Au₁₀ geometry changes from planar to 3D (C_2v symmetry) upon the formation of Au 10 + . Interestingly, Me 11 + clusters have the same symmetry for Au and Ag (C_3h), whereas Cu 11 + has a C₁ symmetry point group.

Therefore, the symmetry of the naked clusters depends on metal type, charge, and atom number. The geometries of Au, Ag, and Cu clusters are similar only in the case of Me 3 + clusters, whereas more complex Me_9–11 ^q clusters are all different (Figure 1). Yet, the similarity between Cu and Ag clusters is observed to a greater or lesser extent. All the observations are in line with the literature data. Obviously, NC symmetry can change upon the interplay with Nep.

3.2 Complexes with magic atom number m* = 2

Optimization of the Nep–Me N q structures has been performed with the PBE-D3/def2-TZVP method. First, the possible interactions between the Nep⁰ and neutral Me₂ clusters were analyzed and Me₂ was placed near the electronegative O and N atoms of Nep⁰. The eight sites of attraction found include N1, H₂N, N5, N8, C═O, as well as O atoms of the side substituent (O1′, O2′, and O3′). The N5 atom has been found to be the most energetically favorable for Au₂ attachment: E _b = 17.3 kcal mol⁻¹. For Ag₂ and Cu₂, the binding energy with Nep⁰ is equal to 7.1 and 19.6 kcal mol⁻¹. Therefore, binding energy decreases in the following order: Cu₂ > Au₂ > Ag₂ (Table 1).

Table 1

Binding energies of metal clusters with Nep (in kcal mol⁻¹) forming complexes with magic atom number 2

	Au ⁰	Au 2 +	Au ₂	Au 3 +
Nep⁰			17.3	35.9
Nep⁻¹	13.1	61.4
	Ag ⁰	Ag 2 +	Ag ₂	Ag 3 +
Nep⁰			7.1	18.6
Nep⁻¹	3.9	29.2
	Cu ⁰	Cu 2 +	Cu ₂	Cu 3 +
Nep⁰			19.6	29.7
Nep⁻¹	25.4	33.8

The neutral Me⁰ atom attaches Nep⁻¹ with the following priority: Cu > Au > Ag. For Me 2 + and Me 3 + clusters, E_b decreases in the order Au > Cu > Ag (Table 1). Regarding the clusters with magic atom number m* = 2, Nep⁻¹– Au 2 + is the most stable complex overall (Figure 2): E _b = 61.4 kcal mol⁻¹. Among Ag and Cu NCs, Nep⁻¹– Ag 2 + and Nep⁻¹– Cu 2 + are also the most stable ones: 29.2 and 33.8 kcal mol⁻¹, respectively. The obvious reason for such large binding energies is electrostatic attraction between a positively charged cluster and a negatively charged organic ligand.

Figure 2

Nep–Me clusters with magic atom number m* = 2.

The N5 site is the most typical for Me attraction since Me forms anchoring Me–O and non-conventional hydrogen bonds with the side-substituent of Nep (the only exception is Nep⁻¹–Au⁰ system where the bonding occurs through the N3 atom of Nep); obviously, the character of Au–N3 binding is different as compared to Au–N5 binding, probably the Au–N3 interaction is more electrostatic. Interestingly, Nep⁻¹– Au 2 + seems not to form neither anchoring bonds with the O′ atoms of the side-substituent nor H bonds (Figure 2); thus, it is a monodentate complex. On the contrary, Nep⁻¹– Cu 2 + forms anchoring bonds with the carbonyl and with O3′ making a tridentate complex. Ag 2 + also forms a bond with the carbonyl of Nep⁻¹ (a bidentate complex).

Therefore, for each complex Nep − Me m q , the most stable geometry is shown in Figure 2, whereas cartesian coordinates are presented in Supplementary Materials. The three most energetically favorable complexes overall are Nep⁻¹– Au 2 + , Nep⁰– Au 3 + , and Nep⁻¹– Cu 2 + . For this reason, these complexes will be regarded in further sections.

3.3 Complexes with magic atom number m* = 10

All the m* = 10 Au and Ag complexes attach metal atoms through the N5 site and are monodentate (Figure 3). The only exceptions are Nep⁻¹– Au 10 + and Nep⁻¹– Ag 10 + systems, which also form Me–O bonds with the carbonyl. The Cu complexes with m* = 10 are all tridentate forming bonds not only with N5 but also anchoring bonds with the carbonyl and O3′. The strongest bonding in terms of Gibbs free binding energy of complexation is observed for the Nep⁻¹–Cu₉ complex: 29.5 kcal mol⁻¹ (Table 2). The most stable Nep–Ag system is Nep⁻¹– Ag 10 + complex: 17.6 kcal mol⁻¹, whereas among Au-containing systems Nep⁻¹– Au 10 + is the most efficient: 23.2 kcal mol⁻¹. The second most stable system is the complex of Nep⁻¹– Cu 10 + : 25.8 kcal mol⁻¹.

$Figure 3 Geometries of Nep − Me N q \text{Nep}{\boldsymbol{-}}{{\rm{Me}}}_{{\rm{N}}}^{{\rm{q}}} (N = 9–11, q = 0, +1) complexes according to PBE-D3/def2-TZVP.$

Figure 3

Geometries of Nep − Me N q (N = 9–11, q = 0, +1) complexes according to PBE-D3/def2-TZVP.

Table 2

Binding energies of metal clusters with Nep (in kcal mol⁻¹) forming complexes with magic atom number m* = 10

	Au ₉	Au 10 +	Au ₁₀	Au 11 +
Nep⁰			12.3	19.2
Nep⁻¹	20.5	23.2
	Ag ₉	Ag 10 +	Ag ₁₀	Ag 11 +
Nep⁰			7.9	10.7
Nep⁻¹	12.1	17.6
	Cu ₉	Cu 10 +	Cu ₁₀	Cu 11 +
Nep⁰			17.1	18.1
Nep⁻¹	29.5	25.8

As it was stated previously, some NCs change symmetry upon the interplay with Nep. Thus, the most stable complex of the Nep⁻¹– Au 10 + (C_3v) cluster is strongly distorted, named symmetry C₁, whereas the naked Au 10 + cluster is C_2v. Ag 10 + also changes its symmetry from D_2d to C₁ upon complexation with Nep⁻¹, whereas Cu 10 + transforms from the D_2d symmetry point group into C_s. Nep⁻¹–Ag₉ changes its symmetry from C_s to C_2v, whereas Au₉ and Cu₉ both remain with C_2v symmetry. On the contrary, Ag₁₀ does not change its D_2d symmetry upon complexation with Nep⁰, whereas Au₁₀ changes from D_3h into C_2v, and Cu₁₀ transforms from D_2d into C_s. All the Me 11 + clusters change their symmetry upon the interaction with Nep. As one can see, the geometry changes more severely in the case of cationic clusters than in the case of neutral NCs. The NCs changing their symmetry point group upon the interaction with pteridine are presented in Table 3. Thus, clusters with m* = 2 do not change the symmetry point group upon the complexation with Nep, whereas the clusters with m* = 8 are largely determined by the symmetry transformation with only a few exceptions: Au₉, Cu₉, and Ag₁₀.

Table 3

Summation of clusters changing (+) and not changing (−) their symmetry upon the binding with Nep

	Au ⁰	Au 2 +	Au ₂	Au 3 +
Nep⁰			−	−
Nep⁻¹	−	−
	Ag ⁰	Ag 2 +	Ag ₂	Ag 3 +
Nep⁰			—	—
Nep⁻¹	−	−
	Cu ⁰	Cu 2 +	Cu ₂	Cu 3 +
Nep⁰			—	—
Nep⁻¹	−	—
	Au ₉	Au 10 +	Au ₁₀	Au 11 +
Nep⁰			+	+
Nep⁻¹	−	+
	Ag ₉	Ag 10 +	Ag ₁₀	Ag 11 +
Nep⁰			−	+
Nep⁻¹	+	+
	Cu ₉	Cu 10 +	Cu ₁₀	Cu 11 +
Nep⁰			+	+
Nep⁻¹	−	+

3.4 QTAIM analysis

QTAIM [54,55] was used to study the properties of metal bonds with Nep. The most stable complexes of Au and Cu with Nep⁻¹ have been regarded. Previously, we have applied QTAIM to study the interactions of amino acids and pterin with Au [33,56] and Ag [32,57]. We have calculated five QTAIM parameters (Table 4): (1) density of all electrons ρ(r), (2) Laplacian of electron density ∇² ρ(r), (3) Lagrangian kinetic energy G(r), (4) potential energy density V(r), and (5) energy density H(r).

Table 4

Bader’s QTAIM theory BCP properties (all in Hartree, whereas bond energy E _bond is in kcal mol⁻¹)

Complex	BCP	P(r)	∇² ρ(r)	G(r)	V(r)	H(r)	E _bond
Nep⁻¹– Au 2 +	Au–N5	0.1112	0.3433	0.1216	−0.1574	−0.3580	49.4
Nep⁻¹– Au 2 +	Au–O	0.0698	0.2202	0.0671	−0.0791	−0.0120	24.8
Nep⁻¹– Au 2 +	Au–O1′	0.0373	0.11730	0.0318	−0.0342	−0.0024	10.7
Nep⁻¹– Cu 2 +	Cu–N5	0.0816	0.3273	0.1036	−0.1253	−0.0217	39.3
Nep⁻¹– Cu 2 +	Cu–O	0.0671	0.3071	0.0908	−0.1047	−0.0140	32.8
Nep⁻¹– Cu 2 +	Cu–O3′	0.0641	0.2938	0.0861	−0.0988	−0.0127	31.0
Nep⁻¹– Au 10 +	Au–N5	0.0762	0.2377	0.0750	−0.0906	−0.0156	28.4
Nep⁻¹– Au 10 +	Au–O	0.0706	0.2507	0.0753	−0.0880	−0.0126	27.6
Nep⁻¹– Au 10 +	Au–O3′	0.0555	0.2104	0.0593	−0.0660	−0.0067	20.7
Nep⁻¹–Cu₉	Cu–N5	0.0953	0.3771	0.1241	−0.1540	−0.0298	48.3
Nep⁻¹–Cu₉	Cu–O	0.0926	0.4860	0.1457	−0.1699	−0.0242	53.3
Nep⁻¹–Cu₉	Cu–O3′	0.0607	0.2905	0.0833	−0.0939	−0.0106	29.5

All bond critical points (BCPs) have a positive Laplacian, which signifies the following: all Me–X (X = O, N, C or H) interactions have an electrostatic nature. Moreover, all BCPs have negative H(r), which signifies that electrostatic bonding stabilizes Me–X interactions. Positive ∇² ρ(r) and negative energy density H(r) for each BCP mean that all Me–X bonds are partially electrostatic and partially covalent. Therefore, QTAIM has shown that the interplay between Nep and Me clusters is partially electrostatic and partially covalent.

The Au–N5 bond (49.4 kcal mol⁻¹) of the Nep⁻¹– Au 2 + system is stronger than the Au–O bond (24.8 kcal mol⁻¹). Me–N bonds are stronger than Me–O also for Nep⁻¹– Cu 2 + and Nep⁻¹– Au 10 + but not for Nep⁻¹–Cu₉. For the Nep⁻¹–Cu₉ complex, the Au–O bond energy is higher than the Au–N5 bond energy: 53.3 and 48.3 kcal mol⁻¹, respectively. Moreover, the Cu–O bond of Nep⁻¹–Cu₉ is the strongest bond overall among all the regarded systems. On the contrary, the anchoring bonds with the side substituent of Nep through Me–O′ is the weakest for each system: the weakest one is observed for Nep⁻¹– Au 2 + (10.7 kcal mol⁻¹), whereas the strongest one is of Nep⁻¹– Cu 2 + (31 kcal mol⁻¹). Thus, bonding energy E _bond has the following order: Me–N5 > Me–O > Me–O′.

Contrary to Gibbs binding energy (Tables 1 and 2), according to QTAIM, the bonding of ultra-small clusters with m* = 2 to Nep is not stronger than the bonding of m* = 10 NCs. The strongest bonding in terms of QTAIM bonding energy is observed for Cu–O in the Nep⁻¹–Cu₉ complex. On average, the bonding of O and N with Cu is stronger than Au–X bonding.

3.5 Absorption spectra of Nep–Me complexes

We have analyzed the first 20 transitions of the naked metal clusters and Nep–Me complexes. As one can see in Figure 4, the Au 2 + cluster possesses a UV–vis spectrum with a strong predominant band at 291 nm with an oscillator strength f _OSC equal to 0.554. Upon the addition of Nep⁻¹, three bands arise in the UV region: at 304 nm (0.125), 326 nm (0.207), and 343 nm (0.202), whereas the long-wave maximum is located at 977 nm (0.055). This signifies that the bathochromic shift of the UV–vis spectrum upon the addition of Nep⁻¹ can be utilized for colorimetric analyte detection. On the contrary, the Cu 2 + spectrum possesses a single dominant transition at 391 nm (0.265); upon the attachment of Nep⁻¹, this spectrum is hypsochromically transformed: two major maxima in the UV region are located at 328 nm (0.191) and 369 nm (0.133), whereas the long-wave maximum is red-shifted to 566 nm (0.013). Apparently, this shift of the spectrum can be utilized for UV–vis detection of Nep using the Cu cluster.

$Figure 4 UV–vis electronic spectra of Nep – Me N q {\text{Nep}\mbox{--}\text{Me}}_{\text{N}}^{\text{q}} complexes according to the M062X/def2-TZVP method. Lorentzian broadening with bandwidth at 0.5 height equal to 15 nm was applied.$

Figure 4

UV–vis electronic spectra of Nep – Me N q complexes according to the M062X/def2-TZVP method. Lorentzian broadening with bandwidth at 0.5 height equal to 15 nm was applied.

The spectrum of the naked Au 10 + is characterized by a major peak at 388 nm (0.236) and a long-wave maximum located at 575 nm (0.014). Upon the complexation with Nep⁻¹, these maxima are bathochtomically shifted to 435 nm (0.097) and 617 nm (0.067), respectively. As a whole, the intensity of electronic transitions lowers with the addition of Nep.

Cu₉ has a major peak located in the visible region at 437 nm (0.237) and long-wave maximum with extremely low intensity: 992 nm (0.004). Upon attachment of Nep⁻¹, these main maxima are shifted to 477 nm (0.055) and 797 nm (0.014); as a whole, the UV–vis spectrum is significantly transformed.

Upon the complexation of a metal NC and an organic molecule, the absorbance peaks should red-shift, since the electronic systems of a molecule and metal atoms unite to form a common entity. This is a well-known effect for similar systems regarding both absorption and fluorescence spectra: for example, Ag and Au clusters in complex with cysteine [58]. Similar effects (bathochromic shift of absorption spectra) were observed for phenylalanine and Au [59]. The larger system of electrons results in a red-shift of the spectra, both absorbance and fluorescence [58]. Indeed, in our case, the spectra of Nep⁻¹– Au 10 + and Nep⁻¹–Cu₉ strongly red-shift upon the complexation of metal NCs with Nep. However, the spectra of Nep⁻¹– Au 2 + and Nep⁻¹– Cu 2 + seem to be blue-shifted. However, it is not absolutely true because the long-wave maxima (at 977 and 566 nm) of the Nep⁻¹– Au 2 + and Nep⁻¹– Cu 2 + clusters (and spectra as a whole) are red-shifted as compared to the isolated Au 2 + and Cu 2 + NCs.

All the above Nep–Me systems possess S₀ → S₁ transitions with zero or minimal intensity, which should them barely legal for luminescent detection of Nep, whereas colorimetric detection seems to be meaningful in each case.

3.6 Raman spectra of the most stable complexes

The Raman spectra of Nep⁻¹ and the most stable complexes with magic atom number m* equal 2 and 10 have been simulated: Nep⁻¹– Au 2 + , Nep⁻¹– Cu 2 + , Nep⁻¹– Au 10 + , and Nep⁻¹–Cu₉. As well known, spectra of naked NCs possess too low intensity, so their spectra are not shown, whereas the Nep⁻¹ spectrum undergoes extremely significant changes upon the interplay with ultra-small and small NCs.

The naked Nep⁻¹ Raman spectrum has four major bands with nearly equal intensity (Figure 5): at 1,330 cm⁻¹ (664 a.u.), 1,601 cm⁻¹ (631 a.u.), 3,088 cm⁻¹ (686 a.u.), and 3,582 cm⁻¹ (725 a.u.). The first band corresponds to “breathing” of the whole pteridine ring system. The 1,601 cm⁻¹ band is responsible for C–NH₂ bond stretching. The 3,088 and 3,582 cm⁻¹ bands are about the C1′–H bond stretching and NH₂ group symmetric stretching, respectively.

$Figure 5 Raman spectra of Nep−1– Au 2 + {\text{Au}}_{2}^{+} (a), Nep−1– Cu 2 + {\text{Cu}}_{2}^{+} (b), Nep−1– Au 10 + {\text{Au}}_{10}^{+} (c), and Nep−1–Cu9 (d) complexes simulated with the B3LYP-D3/def2-TZVP method. Lorentzian broadening was applied with a bandwidth at 0.5 height equal to 30 cm−1.$

Figure 5

Raman spectra of Nep⁻¹– Au 2 + (a), Nep⁻¹– Cu 2 + (b), Nep⁻¹– Au 10 + (c), and Nep⁻¹–Cu₉ (d) complexes simulated with the B3LYP-D3/def2-TZVP method. Lorentzian broadening was applied with a bandwidth at 0.5 height equal to 30 cm⁻¹.

Three major peaks of Nep⁻¹– Au 2 + are following: 3,047 cm⁻¹ (1,125 a.u.), 3,595 cm⁻¹ (1,015 a.u.), and 1,401 cm⁻¹ (950 a.u.). These maxima correspond to C1′–H bond stretching, symmetric amino group stretching, and N8–C7–H scissoring, respectively. As a whole, the Au 2 + cluster does not cause severe transformations of the Raman spectrum.

The spectrum of Nep⁻¹– Cu 2 + also does not differ dramatically from the naked Nep⁻¹. The major maximum is located in the 1,300–1,600 cm⁻¹ region (Figure 5b): it emerges at 1,361 cm⁻¹ (1,251 a.u.) and refers to the “breathing” of pteridine. Thus, this peak undergoes a 31 cm⁻¹ hypsochromic shift and 88% increment of intensity as compared to the bare Nep⁻¹. The second most intense peak is located in the 3,000–3,600 cm⁻¹ region: it is at 3,584 cm⁻¹ (800 a.u.) and refers to the amino group symmetric stretching. Therefore, the Cu 2 + cluster does not bring significant transformations of the Raman spectrum.

The main transformations of the Nep⁻¹ spectrum with the attachment of Au 10 + occur in the range 3,000–3,800 cm⁻¹. The predominant transition of the Nep⁻¹– Au 10 + complex is located at 3,556 cm⁻¹ with a 2,427 a.u. intensity and refers to the O1′–H bond stretching (a 3.3 times chemical enhancement of the signal as compared to the 3,582 cm⁻¹ peak of the naked Nep⁻¹). The second strongest band is at 3,588 cm⁻¹ (1,526 a.u.) and relates to symmetric stretching of the amino group. Thus, the intensity of this peak increases more than two times as compared to the bare Nep⁻¹. The peak at 3,068 cm⁻¹ (1,201 a.u.) relates to C′–H bond stretching of the side substituent. The 1,300–1,600 cm⁻¹ region also possesses intense bands: for example, the 1,445 cm⁻¹ (1,256 a.u.) band refers to the scissoring of the H–C1′–O1′ group. The 1,614 cm⁻¹ (1,247 a.u.) peak is responsible for the C–NH₂ bond stretching. It has already been revealed for the bare Nep⁻¹ spectrum (a band at 1,601 cm⁻¹); thus, it undergoes a 13 cm⁻¹ hypsochromic shift upon the attachment of Au 10 + to Nep⁻¹.

The predominant peak of Nep⁻¹–Cu₉ is located at 3,387 cm⁻¹ (10,283 a.u.). It relates to the O1′–H bond stretching. In the spectrum of the bare Nep⁻¹, this transition is located at 3,671 cm⁻¹ (110 a.u.). This means that upon the attachment of Cu₉, this maximum is bathochromically shifted by 286 cm⁻¹, whereas its intensity is enhanced by 93 times. The second highest maximum is at 1,588 cm⁻¹ (2,654 a.u.), which refers to C6–C7 bond stretching. Cu₉ interacts with all the functional groups of Nep: pyrimidine, pyrazine, and side substituent (Figure 3), which apparently makes Cu₉ a selective and effective tool for Nep in vitro detection.

In real experimental conditions, the spectra are affected by other molecules, both low-molecular-weight compounds and biopolymers. Usually, performing the detection of pterin in aqueous solutions, we determine the optimal experimental conditions for cluster synthesis and pterin detection: this includes concentrations, pH, temperature, time of preparation, etc. [60]. When a protocol for pterin detection is determined, one may start to perform the experiments in biological liquids, for example, in human serum. Specific experimental conditions allow us to determine specific compounds (pterins) in the presence of other molecules. Moreover, when one utilizes Raman spectroscopy, it allows one to determine particular fingerprints of specific biomolecules [61], yielding unique Raman maxima and signal shifts. That is why SERS has attracted the attention of the researchers in recent years [62]. SERS allows thdetermination of specific substances in biological liquids even with a femtomole level limit of detection [63].

Analysis of the Raman spectra shows that complexes with m* = 10 are more promising tools for the experimental detection of Nep at alkaline pH than m* = 2 clusters. For example, the Cu₉ cluster causes more than 90 times enhancement of the Raman signal.

3.7 NBO analysis

The chemical enhancement of the SERS signal can be expressed in terms of ground state charge transfer (CT) [64]. Thus, NBO analysis was used to evaluate ground-state CTs. Since NBO analysis was used to study SERS effects, the NBO parameters with the B3LYP-D3/def2-TZVP method was obtained. The B3LYP functional has already demonstrated its accuracy for the NBO analysis of similar systems [32,65,66,67].

The two most stable Nep–Me complexes with m* = 2 (Nep⁻¹– Au 2 + and Nep⁻¹– Cu 2 + ) and m* = 10 (Nep⁻¹– Au 10 + and Nep⁻¹–Cu₉) have been regarded. Second-order perturbation theory analysis of the Fock matrix in NBO basis data is demonstrated in Table 5. The NBO analysis revealed the following about intracomplex bonding. Briefly, the higher value of E ⁽²⁾ demonstrates the greater donation of the i orbital since the more intense the interaction between the electron donor i and acceptor j orbitals [68]. In this particular case, the most significant intracomplex interplay of Au, Cu, and Nep is revealed in the orbital overlap between n and n* orbitals. Therefore, ground-state CTs result in the stabilization of the whole complexes and lead to an enlargement of electron density in the antibonding orbital.

Table 5

Second-order perturbation theory study of the Fock matrix in the NBO basis for the most stable Nep–Me systems

Complex	Donor (i)	Orbital type	Occupancy	Acceptor (j)	Orbital type	Occupancy	E ⁽²⁾, kcal mol⁻¹	q _CT
Nep⁻¹– Au 2 +	N5	n	0.846	Au	n*	0.065	15.26	0.053
Nep⁻¹– Cu 2 +	N5	n	0.899	Cu	n*	0.120	22.36	0.162
Nep⁻¹– Cu 2 +	O3′	n	0.931	Cu	n*	0.065	15.44	0.106
Nep⁻¹– Au 10 +	N5	n	0.900	Au	n*	0.062	5.66	0.016
Nep⁻¹–Cu₉	N5	n	0.885	Cu	n*	0.075	22.29	0.079
Nep⁻¹–Cu₉	O	n	0.917	Cu	n*	0.051	19.51	0.066
Nep⁻¹–Cu₉	O3′	n	0.941	Cu	n*	0.047	12.57	0.041

Table 5 represents E ⁽²⁾ and q _CT values for the maximal ground state CTs (the highest E ⁽²⁾ values for concrete complexes) with the participation of metal. Most CTs occur between metal atoms and N5 of Nep. For example, the n_N5 → n Au ⁎ CT takes place in the Nep⁻¹– Au 2 + system (E ⁽²⁾ = 15.26 kcal mol⁻¹, q _CT = 0.053). This ground state CT could be responsible for the “breathing” of the whole system in the Raman spectrum. Other ligand–metal CTs of this complex are too small in terms of stabilization energy and are not mentioned.

Another example is that the ligand–metal CT complex is a n_O3′ → n Au ⁎ delocalization of the Nep⁻¹– Cu 2 + , which is characterized by E ⁽²⁾ = 15.44 kcal mol⁻¹ and q _CT = 0.106. This is significantly smaller than the stabilization energy of the n_N5 → n Cu ⁎ CT (22.36 kcal mol⁻¹ and q _CT = 0.162).

Regarding complexes with m* = 10, small CTs are equally distributed among various atoms and orbitals in the Nep⁻¹– Au 10 + complex; for this reason, the largest stabilization energy is observed for the n_N5 → n Au ⁎ CT: 5.66 kcal mol⁻¹. On the contrary, Nep⁻¹–Cu₉ is stabilized by several significant CTs (Figure 6): n_N5 → n Cu ⁎ , n_O → n Cu ⁎ , and n_O3′ → n Cu ⁎ with E ⁽²⁾ equal to 22.29, 19.51, and 12.57 kcal mol⁻¹, respectively. Thus, the character of CTs for Au and Cu is determined by the fact that Au complexes are basically monodentate, whereas Cu complexes are mostly tridentate.

Figure 6

Selected natural bond orbitals for ligand–metal CTs of the Nep⁻¹–Cu₉ complex.

4 Conclusion

The interactions between Nep and coinage metal (Au, Ag, and Cu) NCs were studied using the methods of quantum chemistry and DFT. In particular, the geometries and symmetry of the most stable naked clusters have been obtained. The symmetry of an isolated cluster depends on metal type, charge, and number of atoms. The most stable geometries of the naked clusters and clusters in complex with Nep are mostly different: upon complexation with Nep, the geometries change more significantly in the case of q = +1 clusters than in the case of neutral ones.

Gibbs free energies of complexation for complexes of Me N q clusters with neutral Nep⁰ and deprotonated Nep⁻¹ were determined. The most energetically favorable complexes have been established. The highest binding energy has been found for the Nep⁻¹– Au 2 + system: 61.4 kcal mol⁻¹. In each case, metal atoms bond with the N5 atom of Nep (a single exception is Nep⁻¹, which binds Au⁰ through N3). Cu clusters bind simultaneously to N5, O, and O3′ atoms of Nep, whereas the complexes of Au and Ag are mostly monodentate. As a rule, the complexes of Nep⁻¹ are more stable than Nep⁰-containing complexes.

UV–vis absorption and Raman spectra have been calculated for a set of the most stable complexes with magic atom numbers m* = 2, 10: Nep⁻¹– Au 2 + and Nep⁻¹– Cu 2 + , Nep⁻¹– Au 10 + , and Nep⁻¹–Cu₉, respectively. The electronic UV–vis spectra of the complexes are located mostly in the UV region. Upon complexation with Nep⁻¹ oscillator strength diminishes nearly two times, whereas the spectrum is bathochromically or hypsochromically shifted, which opens some prospects for colorimetric detection of Nep.

Nep levels in blood serum are in the nM range [69]. These levels can be barely detected using absorption spectroscopy. However, Raman spectroscopy and SERS open many possibilities in detecting pterins and other biomarkers: SERS permits a 10²–10⁶-times chemical/electromagnetic signal enhancement [64]. Moreover, one can use aptamer-based [70] technology to develop nanosensors for Nep detection. Thus, this study opens many perspectives for pterin sensing in the future. Detection of Nep using SERS is the most promising using copper since the Nep spectrum undergoes significant chemical enhancement and maxima shift upon complexation with Cu₉.

Nep detection in biological samples is of great necessity in medicine, and improvement of experimental techniques for Nep determination is much needed. The theoretical analysis has shown that the usage of copper, Au, and Ag NCs and nanoparticles is a promising tool for the detection of Nep biomarkers. It shows the possibility of NCs application in vitro using Raman spectroscopy and tunable colorimetry.

Funding information: The research was funded by the Russian Science Foundation, grant number 20-73-10029, https://rscf.ru/project/20-73-10029/.
Author contributions: Andrey A. Buglak is responsible for the entire work.
Conflict of interest: The author states no conflict of interest.
Data availability statement: The datasets generated during and/or analysed during the current study are available from the corresponding author on reasonable request.

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Received: 2023-10-16

Revised: 2025-02-17

Accepted: 2025-05-22

Published Online: 2025-06-18

This work is licensed under the Creative Commons Attribution 4.0 International License.

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Keywords for this article

neopterin; metal nanoclusters; density functional theory; SERS; metal–ligand interactions

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