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Chemical identification of the amyloid peptide aggregation-prone Al(III)-peptide complexes by resonance Raman signatures: A computational study
Chemical Physics 513 (2018) 1–6
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Chemical Physics journal homepage: www.elsevier.com/locate/chemphys
Chemical identification of the amyloid peptide aggregation-prone Al(III)peptide complexes by resonance Raman signatures: A computational study ⁎
Baoling Tiana, Changhang Chengb, Tongtao Yueb, Na Linc, , Hao Renb,
T
⁎
a
College of Chemistry and Pharmaceutical sciences, Qingdao Agricultural University, Qingdao 266109, PR China Center for Bioengineering and Biotechnology, College of Chemical Engineering, China University of Petroleum (East China), Qingdao 266580, PR China c State Key Laboratory of Crystal Materials, Shandong University, Jinan 250204, PR China b
A B S T R A C T
The aggregation of amyloid peptides as fibril-like β-sheet conformers is of vital importance in the development of Alzheimer’s disease. It has been experimentally shown that Al(III) ions are aggregation-prone for amyloid peptides. Recently, it was proposed that Al(III) can directly bond to the peptide backbone and forming a ring structure. This ring structure drastically alters the secondary structure of the amyloid fibrils and induces irreversible denaturation. However, the kinetics and dynamics of Al(III)-peptide binding is still not well understood, which requires the detailed knowledge of the geometric and electronic structures of the binding intermediates and the products. In the present work, based on simple molecular models, we performed ab initio calculations for the spontaneous resonance Raman (RR) spectroscopic signals. The Raman characteristics of the complexes are distinct enough for chemical identification. All these features can be related to the vibronic coupling between the vibrational fingerprints and the specific electronic transitions. The rich structural information contained in the RR signals enables us to identify and characterize the Al(III)-peptide complexes at low concentrations typically in life sciences.
1. Introduction Neurodegenerative diseases such as Alzheimer’s disease (AD), prion disease and Parkinson’s disease are seriously threatening the human health [1–4]. These diseases usually involve protein misfolding where normally soluble proteins aggregate as abnormally insoluble amyloid fibrils that disrupt the tissue structure and cause disease [5]. It is well known that amyloid fibrils mainly consists of cross-β structures [6]. It has a core formed by antiparallel β sheets perpendicular to the long axis of fibril. The deposition of amyloid as β-sheet (Aβ) conformers associated with the appearance of senile plaques is frequently observed as a significant risk factor for the AD [7]. Metal ions, primarily aluminum, iron, zinc, and copper have been widely demonstrated to be potential risk cofactors in neurodegenerative disorder diseases [8,9]. Postmortem analysis of brain tissues from patients with neurodegenerative disorders confirmed the involvement of these ions, such as triggering structural transformation or aggregation, and co-depositing with Aβ in vitro [10,11]. Among these ions, Al(III) is the most harmful to accelerate the formation of Aβ fibrils [12,13]. Recent experiments suggested that aluminum should now be considered as a primary etiological factor in AD [14–16]. Detailed molecular mechanism of the Al(III) induced
⁎
Corresponding authors. E-mail addresses: [email protected] (N. Lin), [email protected] (H. Ren).
https://doi.org/10.1016/j.chemphys.2018.06.006 Received 14 April 2018; Accepted 13 June 2018 Available online 19 June 2018 0301-0104/ © 2018 Elsevier B.V. All rights reserved.
neurotoxicity and protein misfolding would be significant to reveal the physiology and pathology of AD, and might facilitate the diagnosis or provide clues for the treatment. The interaction of the Al(III) ions with amyloid peptides is crucial to understand its role in the development of AD. Recently, Song et al. suggested a new interaction paradigm for Al(III) ion binding to peptide bonds [17], where the Al(III) ion could directly interact with the peptide carbonyl and amino groups, forming stable structures with a characteristic five-member ring in a wide range of peptides, especially for neurodegenerative disease related motifs. This is a direct consequence of the fact that Al(III) ions can simultaneously bond to the amide nitrogen and carbonyl oxygen atoms. This type of binding motif would lead to a dramatic change of the secondary structure, followed by conformation alteration and denaturation. On the other hand, Mujika et al. claimed that the preferential binding site of Al(III) on proteins would at the side chain, and it was difficult to reconcile the backbone binding motif [18]. The formation of the aluminum-induced backbone ring structures has not been confirmed by other works so far. Appropriate characterization tools for these ring conformations are required to resolve this controversial issue. Resonance Raman (RR) spectroscopy is a powerful tool to
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Fig. 1. A hydrated aluminum ion binds to a peptide backbone and forms a ring structure. a) The initial state: a peptide segment HCO–Ala–NH2 and a hydrated Al(III) ion [AlOH(H2 O)4]2 + far away to each other; b) Complex I: binding of the Al(III) ion with the O2 atom in the peptide carbonyl group; c) Complex II: simultaneous binding of the Al(III) ion with the amide N1 and the carbonyl O2. The gray, blue, red, white, and pink balls represent C, N, O, H, and Al, respectively. (For interpretation of the references to colour in this figure legend, the reader is referred to the web version of this article.)
Here μ is the electronic transition dipole moment; ℏω1, ℏωri are the incident photon energy and the energy difference between the intermediate state |r 〉 and the initial state i〉. We only consider the first order Franck–Condon (FC) contribution to the RR signals in this work, since the higher order Herzberg-Teller terms only contribute slightly for strongly allowed electronic transitions [29–32]. The vibrational linewidth Γr = 10 cm−1 is used for the intermediate vibronic states. We aimed to identify the different Al(III)-peptide binding complexes by their RR characteristics that are correlated to the binding structures. To examine the excitation dependent vibronic effects, we constructed simple molecular models to capture the geometric configurations and the local chemical environments of the binding complexes according to previous calculations [17]. The two model structures corresponding to the intermediate binding complex and the five-membered ring, as well as a model peptide HCO–Ala–NH2 served as a reference for a typical peptide chain, are depicted in Fig. 1. For clarity, we named these complexes as complex I, complex II, and Ala, respectively. In addition to the peptide segment, we also placed a hydrated Al(III) ion near the peptide. The hydrate aluminum ion has the formula [Al(OH)(H2 O)4]2 + that widely exists in biological systems [33]. During the Al(III) induced protein denaturation, the hydrated Al(III) ion firstly interacts with the peptide carbonyl oxygen atom, and forms complex I. In the meantime, one water molecule initially coordinated to the Al(III) center is released, results in a lower coordinate number of 4 as shown in Fig. 1(b). The Al(III) ion in complex I can further bond to the neighboring amide nitrogen atom N1 to form complex II (see Fig. 1(c)). Here, the hydrogen atom H1 initially bound to N1 is substituted by the Al ion, together with the released water molecule initially bound to the Al(III) center, in the form of hydrate proton [H3 O]+. The formation of the ring structure in complex II would induce a dramatic change in the secondary structure, which would promote the aggregation of amyloid peptides. We used the Gaussian 09 package [34] with the (time-dependent) density functional theory (TD-DFT), the PBE0 hybrid functional [35–37] and the 6–311++G(d, p) basis set [38] in all the calculations. The geometries were optimized to minimize the ground state energy and forces at which excited state gradients and displacements were calculated [21]. The polarizable continuum model with conductor-like solvation (CPCM) [39,40] was used to perform the self-consistent reaction field (SCRF) calculations to simulate the aqueous environment. We performed natural transition orbital (NTO) [41] analysis for the electronic transitions. To correct the systematic error in the density functional frequency calculations, we scaled all the vibrational frequencies by a factor of 0.97 [42]. In the calculation of the UV-vis absorption spectra, we used the cumulant expression to bypass the
characterize the electronic and geometric structures of complex systems, thanks to its intrinsic selectivity upon electronic transitions and its sensitivity to the local chemical environment of the samples [7,19–26]. In RR measurements, electronic transitions with specific spatial or energetic localization characters can be selected by carefully tune the excitation wavelength. The resonant condition would enhance the scattering intensities by a factor greater than 106 [19]. Vibrational modes strongly coupled to the selected electronic transitions can then be detected by measuring the scattered light. It has been shown that peptide or side-chain vibrations can be selectively enhanced by tuning the excitation wavelength resonant with the interested electronic transitions, enabling the characterization of protein secondary structures [27]. In addition, unlike infrared spectra, the O–H bending mode of water is not Raman active, which will not overlap with typical peptide Raman bands, making RR suitable for biological systems in aqueous environment. In this paper, we performed ab initio calculations for the Resonance Raman spectra of the previously proposed complexes appeared during the Al(III)-peptide binding, and illustrates that the RR signals contain detailed structural information of these complexes. Distinct features in the RR spectra can be directly related to the vibronic excitations of each binding complex. 2. Computational protocol The resonance Raman process involves an electronic (and probably a vibronic) excitation from the ground electronic state followed by an emission back to a vibrational state in the ground electronic manifold. The difference in the initial and the final states produces the inelastic character of the Raman scattering. The differential Raman scattering cross section is given by [28], 2 Ifi dσ π 2 ∼3 ν0 ν fi αfi fi (T ) = = 2∼ dΩ I0 ∊0
(1)
where I0 and Ifi are the excitation and scattered wave intensities of the Raman process with the initial state i〉 and the final state |f 〉. ∊0 is the νfi are the excitation and scattered frevacuum permittivity, ∼ ν0 and ∼ quencies (in wavenumbers), respectively. fi (T ) is the occupation probability of the state i〉 at the temperature T, and αfi is the transition polarizability. At resonance, the transition polarizability can be written as,
αfi =
1 ℏ
∑ r
〈f μ r 〉〈r μ i〉 . ωri−ω1−iΓr
(2) 2
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Fig. 2. Vibrational resolved UV-vis absorption spectra of Ala (a), Complex I (b) and Complex II (c). The total absorption spectra are plotted in black. Electronic excitations with significant contributions labeled by εiS , which denotes the i-th electronic transition in system S, are also provided.
absorption spectrum, and ε5A contributes the most significant feature around 60,000 cm−1. The NTOs of the electronic excitations correspond to the four strongest excitations are depicted in Fig. 3(a). It is obvious that the absorption of Ala resembles the typical peptide UV-vis patterns, where the absorption peaks in the deep UV region originate from the peptide n-π∗ and π-π∗ electronic transitions [22]. This spectrum can be used as a reference to select appropriate excitation wavelengths for the RR measurements of complex I and II in the following. As shown in Fig. 2(b), four excitations contribute significantly to the total UV-vis spectrum of complex I. Compared to the absorption of Ala, ε7I can be ascribed to the peptide transition, which possesses similar excitation wavelengths of the strongest feature of Ala (Fig. 1(a)). The
summation over infinite terms [23,43], where the electronic linewidth was taken to be 100 cm−1. 3. Results and discussion 3.1. UV-vis absorption We first examined the UV-vis absorption of the complexes to check the possible excitation wavelengths for RR characterization. For clarity, we denote the i-th electronic transition of the system S as εiS . The vibration resolved UV absorption spectra of Ala are shown in Fig. 2(a). Four excitations contribute significantly to the total UV-vis
Fig. 3. The spatial distribution of NTOs of Ala (a), Complex I (b) and Complex II (c). 3
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Fig. 4. 2DSRR spectra of Ala (a), Complex I (b) and Complex II (c). The horizontal and vertical axes represent the Raman shift and the excitation energy, respectively.
other pronounced features are the consequence of the existence of the hydrated Al(III) ion and its binding with the peptide carbonyl oxygen atom. There are three weaker absorption bands at the low-frequency (long-wavelength) side of the peptide transition: ε2I at 221.79 nm, ε3I at 209.62 nm, and ε5I at 180.99 nm. Combining with the NTO plots shown in Fig. 3(b), these newly appeared features can be ascribed to the amide-Al charge transfer transitions. In detail, during the ε2I transition, charge transfers from the distant peptide bond to the hydrated Al(III)carbonyl region; during the ε3I transition, charge transfers from the Albonded carbonyl and the nearby amide to the metal ion; and for the ε5I transition, charge transfers from the Al-peptide region to the two distant water groups. The charge transfer characteristics of the electronic transitions indicate that the hydrated Al(III) ion strongly interacts with the peptide backbone, which agrees well with previous results [17]. The excitation resolved UV-vis spectra of complex II are shown in Fig. 2(c). Different from the spectra of Ala and complex I, the feature around 60,000 cm−1 (ε7II ) is much narrower than those of the former two systems. It is the consequence of the formation of the Al-peptide five-membered ring. The electronic transitions are localized on the peptide bonds in the former two systems, but is perturbed by the Al(III) contained ring structure. The corresponding NTO plot in Fig. 3(c) demonstrates that this excitation is localized at the ring structure. This localization eliminates the high-frequency C–H or N–H stretching modes, and restricts high probable vibronic excitations to low-frequencies, results in the much narrower peak width. The other features are also originate from excitations involving the ring structure. For instance, the weak peak around 48,000 cm−1 (ε1II ) corresponds to a charge transfer from the Al–N bond to the Al–O bond; the ε5II transition has a slight charge transfer from the ring structure to the peptide back bone. Although the UV-vis absorption spectra of complexes I and II both have distinct features compared to the typical peptide absorption patterns, it is not sufficient to identify these complexes only by UV-vis measurements. The concentration of these complexes would be at the nanomolar level and in a peptide abundant environment, the signal-tonoise ratio of the UV-vis characteristics would be too low to detect. However, the distinctions in the excitation energies and transition characteristics provide the possibility to identify the correlation between the structures and vibronic signals by using resonance Raman.
(2DSRR) spectra of Ala and the binding complexes are shown in Fig. 4. The 2DSRR signals can be viewed as a two-variable function, with the Raman shift as one independent variable (horizontal axis) and the excitation energy as the other (vertical axis). By fixing the excitation energy, we obtain a horizontal slice represent the corresponding resonance or pre-resonance Raman spectrum. We selected a series of RR spectra and plotted them in Fig. 5, these slices are excited with lasers resonant with the typical electronic transitions discussed above. The 2DSRR patterns can also be sliced in the vertical direction, where the Raman shift is fixed. In this manner, we get the Raman excitation profile corresponding to a specific vibration mode. Another interesting pattern in the 2DSRR spectra is the peaks along the diagonal (tilted to the top right) direction. These strong peaks have coordinates (ν , ε + ν )
3.2. Resonance Raman characteristics
Fig. 5. RR spectra with selected excitation energies of Ala (a), Complex I (b) and Complex II (c). The excitation energies are selected to be resonant to those of strong electronic transitions labeled by εiS .
The calculated two-dimensional spontaneous resonance Raman 4
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in the 2DSRR spectra, where ν is the Raman shift (horizontal variable) and ε is the electronic transition energy (vertical variable). These patterns can be ascribed to the resonance enhancement of a specific vibration mode by a 1 ← 0 vibronic excitation in the manifold of the electronic transition ε [23]. We should note that these peaks lie exactly on the diagonal direction is the result of the approximations we adopted. In the Raman calculations, we used the linearly coupled harmonic model [44,45] and neglected the Duschinsky rotations, hence the vibration modes are exactly the same for all the electronic states. By considering the variation of the curvatures of the electronic potential energy surfaces and the Duschinsky rotations, the vibration modes would be linearly combined, and the new frequencies would be slightly shifted. As a result, the tilted patterns would appear in the vicinity of the diagonal direction, and the overall 2DSRR pattern would not change significantly. The 2DSRR patterns of the Ala and the two binding complexes exhibit distinct features both in the Raman profiles and the RR spectra. These distinctions originate from the differences in the electronic excitations (Fig. 2), in the molecular vibrations, and in the coupling between them. All these information can be directly correlated to the geometric configurations of the complexes and the local chemical environments they reside in. We first examine the 2DSRR patterns vertically, i.e. the Raman profiles. The Raman profile of a vibration mode can be viewed as an electronic absorption dressed by the vibronic coupling between this vibration mode and the electronic excitations involved in. Therefore, the Raman profiles resemble the main features of the electronic spectra shown in Fig. 2. In Fig. 4(a), all the strong signals appear in the region with excitation energies higher than 58,000 cm−1, which correspond to the peptide absorption peaks in Fig. 2(a). There are also weaker features in the range 50,000–58,000 cm−1, which are the consequence of the coupling between the vibration modes and ε2A, ε3A , and ε4A . These transitions contribute to the lower-energy tail of the Ala main absorption peak. The 2DSRR spectrum of complex I shown in Fig. 4(b) presents a very different pattern compared to that of Ala. The features with excitation energies above 58,000 cm−1 are similar, with those of complex I slightly blue shifted, while the patterns below 58,000 cm−1 are totally different. The features with lower excitation energies are ascribed to the vibronic coupling with the charge transfer transitions, such as ε2I , ε3I , and ε5I . In Fig. 4(c), strong features appear in the excitation range above 54,000 cm−1. These features are the results of the high probable electronic transitions ε4II , ε5II , ε7II , and those with even higher excitation energies. Obviously, both the Al-O bonding in complex I and the formation of the ring structure in complex II brings considerable RR characteristics for chemical identification. We then discuss the 2DSRR features horizontally, in which case a series of electronic excitations were specified, and the horizontal slices represent the vibration mode dependent vibronic coupling with the particular electronic transitions. The resonant condition of RR measurements enforces that the RR intensity be proportional to the square of the transition dipole. This would amplify the difference in the magnitude of RR signals correspond to different electronic excitations. The RR spectra with selected excitation wavelengths are depicted in Fig. 5, where weaker signals were re-scaled for better visibility. Fig. 5(a) depicts the RR spectra excited with wavelengths resonant with the ε2A, ε3A , and ε4A transitions. All these spectra resemble the typical peptide RR features [46–49,22], i.e. the AmI bands at 1707 and 1685 cm−1, correspond to the carboxyl stretching modes at the N- and C-terminus, respectively; the AmII bands around 1494 cm−1; the AmIII modes around 1200 cm−1; and the Cα −H modes around 1380 cm−1. We also note that the C2–C3 stretching mode at 713 cm−1 has a much stronger relative intensity for ε5A than excited with ε2A and ε3A , as a result of the significant localization of the electron and the hole states at the C2–C3 bond in the ε5A transition (see Fig. 3(a)). Other notable RR features are listed in Table 1. The RR spectra of (Ala)2 provide a reference as the standard peptide RR features in this simulation.
Table 1 Raman active modes of Ala. All frequencies are wavenumbers. Frequency/cm−1
Description
1708 1685 1574 1495 1387 1245 1195 1113 713
AmI at the C-terminus AmI at the N-terminus N–H bending at the N-terminus AmII Cα –H bending AmIII of the N-terminus part AmIII of the C-terminus part C2–C4 stretching C2–C3 stretching combined with N2–H bending
Table 2 Raman active modes of Complex I. All frequencies are wavenumbers. Frequency/cm−1
Description
1691 1659 1501 1481 1371 1278 1224 1111 832
AmI at the C-terminus AmI at the N-terminus AmII at the C-terminus AmII at the N-terminus C1–H bending C2–H bending AmIII out-of-phase Al–O2 and O2–C3 stretching C3–C2 stretching
Three RR spectra of complex I resonant with ε2I , ε3I , and ε5I are presented in Fig. 5(b), and the corresponding vibration modes are listed in Table 2. The common feature of these spectra is the doublets appear at 1500 and 1480 cm−1, which are ascribed to the AmII mode near the C- and N-terminus, respectively. The latter mode is red-shifted due to the increasing of effective mass of the oscillator upon Al(III) bonding. Another characteristic feature is the out-of-phase combination of Al–O2 and C3–O2 stretching modes at 1111 cm−1. The AmI bands also splits into two peaks at 1691 and 1659 cm−1, as a result of the fact that the Nterminus carbonyl is bonded to the Al(III). Since the electron state of ε2I is localized at the hydrated Al(III) and the N-terminus of the peptide, the C-terminus AmI band is much weaker than those of the other excitations. The RR spectra of complex II resonant with ε1II , ε5II and ε7II are shown in Fig. 5(c). We note that the ε1II excited RR spectrum is weaker due to the weak electronic transition. As the result of the formation of the ring structure, which involves the Al(III) ion and the N-terminus carbonyl group, the AmI band corresponds to this carbonyl is significantly hindered. The common feature of the selected RR spectra is the triplet at 1255, 1284, and 1310 cm−1, correspond to the Cα −H mode decorated by the ring distortions. The C2–C3 stretching mode fixed by the ring structure would also be characteristic if the excitation laser is tuned to be resonant with excitations consist considerable contributions from the C2–C3 bond (Fig. 5(c)). For instance, part of the hole state of the ε1II transition is localized on the C2–C3 bond, leading to a sharp peak at 1466 cm−1. The formation of the ring structure also provide another feature in the range 1050–1130 cm−1, coming from the in-plane distortion modes of the Al-peptide ring.Table 3. Both the RR characteristics of the complexes I and II have distinct features compared to those of the Ala, which represents the typical peptide signals in this work. It is even more important that the characteristic RR features of complexes, such as the combined Al–O2 and C3–O2 stretching of the complex I and the ring-distortion related triplet of the complex II, do not overlap with any peptide Raman bands. Considering the resonance enhancement of the RR signals, these RR features would be detectable even in a peptide abundant environment, making RR suitable to chemically identify these complexes.
5
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Table 3 Raman active modes of Complex II. All frequencies are wavenumbers. Frequency/cm−1
Description
1681 1656 1548 1467 1398 1310 1285 1255 1128 1099, 1055 944 763
AmI at the C-terminus C3–N2 stretching coupled with N2–H bending AmI at the N-terminus (in ring) C2–C3 stretching (in ring) C1–H bending Cα 2–H bending coupled with C1–N1 stretching Cα 2–H bending coupled with Al–N1 stretching Cα 2–H bending coupled with C3–O2 stretching N1–Al stretching coupled with N1–C2 stretching Al-peptide ring in-plane torsion Al–N1 stretching Al-peptide ring out-of-plane torsion
[3] [4] [5] [6] [7] [8] [9] [10] [11] [12] [13] [14] [15] [16] [17]
4. Conclusions
[18] [19]
We calculated the vibrational resolved UV-vis absorption and the RR spectra of the Al(III)-peptide binding complexes by using simple molecular models. The complexes I and II are proposed to be crucial in the binding dynamics between Al(III) and peptide backbones, which would lead to the aggregation of amyloid peptides. The detailed vibronic patterns are discussed and their correlation to the geometric and electronic structures, as well as the local chemical environments are illustrated. Using the HCO–Ala–NH2 model as a reference to typical peptides, each complex has characteristic vibronic features and would be detectable with the help of the resonant enhancement in RR measurements. RR is a powerful tool for the chemical identification of samples at low concentrations usually encountered in the study of life sciences. Complimentary to conventional NMR, EPR, and XRD measurements, together these techniques can be used to reveal the microscopic dynamical details of the Al(III)-peptide binding and induced aggregation.
[20] [21] [22] [23] [24] [25] [26] [27] [28] [29] [30] [31] [32] [33] [34]
[35] [36] [37] [38] [39] [40] [41] [42] [43]
Acknowledgments We acknowledge the financial support from the National Natural Science Foundation of China (NSFC, Grant No. 21773309, 21573129, and 21403300), the China Postdoctoral Science Foundation (Grant No. 2014M560587), and High-level Science Foundation of Qingdao Agricultural University (663/1114351). Part of the calculations were carried out at the National Supercomputing Center in Shanghai.
[44] [45] [46] [47] [48]
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Chemical Physics journal homepage: www.elsevier.com/locate/chemphys
Chemical identification of the amyloid peptide aggregation-prone Al(III)peptide complexes by resonance Raman signatures: A computational study ⁎
Baoling Tiana, Changhang Chengb, Tongtao Yueb, Na Linc, , Hao Renb,
T
⁎
a
College of Chemistry and Pharmaceutical sciences, Qingdao Agricultural University, Qingdao 266109, PR China Center for Bioengineering and Biotechnology, College of Chemical Engineering, China University of Petroleum (East China), Qingdao 266580, PR China c State Key Laboratory of Crystal Materials, Shandong University, Jinan 250204, PR China b
A B S T R A C T
The aggregation of amyloid peptides as fibril-like β-sheet conformers is of vital importance in the development of Alzheimer’s disease. It has been experimentally shown that Al(III) ions are aggregation-prone for amyloid peptides. Recently, it was proposed that Al(III) can directly bond to the peptide backbone and forming a ring structure. This ring structure drastically alters the secondary structure of the amyloid fibrils and induces irreversible denaturation. However, the kinetics and dynamics of Al(III)-peptide binding is still not well understood, which requires the detailed knowledge of the geometric and electronic structures of the binding intermediates and the products. In the present work, based on simple molecular models, we performed ab initio calculations for the spontaneous resonance Raman (RR) spectroscopic signals. The Raman characteristics of the complexes are distinct enough for chemical identification. All these features can be related to the vibronic coupling between the vibrational fingerprints and the specific electronic transitions. The rich structural information contained in the RR signals enables us to identify and characterize the Al(III)-peptide complexes at low concentrations typically in life sciences.
1. Introduction Neurodegenerative diseases such as Alzheimer’s disease (AD), prion disease and Parkinson’s disease are seriously threatening the human health [1–4]. These diseases usually involve protein misfolding where normally soluble proteins aggregate as abnormally insoluble amyloid fibrils that disrupt the tissue structure and cause disease [5]. It is well known that amyloid fibrils mainly consists of cross-β structures [6]. It has a core formed by antiparallel β sheets perpendicular to the long axis of fibril. The deposition of amyloid as β-sheet (Aβ) conformers associated with the appearance of senile plaques is frequently observed as a significant risk factor for the AD [7]. Metal ions, primarily aluminum, iron, zinc, and copper have been widely demonstrated to be potential risk cofactors in neurodegenerative disorder diseases [8,9]. Postmortem analysis of brain tissues from patients with neurodegenerative disorders confirmed the involvement of these ions, such as triggering structural transformation or aggregation, and co-depositing with Aβ in vitro [10,11]. Among these ions, Al(III) is the most harmful to accelerate the formation of Aβ fibrils [12,13]. Recent experiments suggested that aluminum should now be considered as a primary etiological factor in AD [14–16]. Detailed molecular mechanism of the Al(III) induced
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Corresponding authors. E-mail addresses: [email protected] (N. Lin), [email protected] (H. Ren).
https://doi.org/10.1016/j.chemphys.2018.06.006 Received 14 April 2018; Accepted 13 June 2018 Available online 19 June 2018 0301-0104/ © 2018 Elsevier B.V. All rights reserved.
neurotoxicity and protein misfolding would be significant to reveal the physiology and pathology of AD, and might facilitate the diagnosis or provide clues for the treatment. The interaction of the Al(III) ions with amyloid peptides is crucial to understand its role in the development of AD. Recently, Song et al. suggested a new interaction paradigm for Al(III) ion binding to peptide bonds [17], where the Al(III) ion could directly interact with the peptide carbonyl and amino groups, forming stable structures with a characteristic five-member ring in a wide range of peptides, especially for neurodegenerative disease related motifs. This is a direct consequence of the fact that Al(III) ions can simultaneously bond to the amide nitrogen and carbonyl oxygen atoms. This type of binding motif would lead to a dramatic change of the secondary structure, followed by conformation alteration and denaturation. On the other hand, Mujika et al. claimed that the preferential binding site of Al(III) on proteins would at the side chain, and it was difficult to reconcile the backbone binding motif [18]. The formation of the aluminum-induced backbone ring structures has not been confirmed by other works so far. Appropriate characterization tools for these ring conformations are required to resolve this controversial issue. Resonance Raman (RR) spectroscopy is a powerful tool to
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Fig. 1. A hydrated aluminum ion binds to a peptide backbone and forms a ring structure. a) The initial state: a peptide segment HCO–Ala–NH2 and a hydrated Al(III) ion [AlOH(H2 O)4]2 + far away to each other; b) Complex I: binding of the Al(III) ion with the O2 atom in the peptide carbonyl group; c) Complex II: simultaneous binding of the Al(III) ion with the amide N1 and the carbonyl O2. The gray, blue, red, white, and pink balls represent C, N, O, H, and Al, respectively. (For interpretation of the references to colour in this figure legend, the reader is referred to the web version of this article.)
Here μ is the electronic transition dipole moment; ℏω1, ℏωri are the incident photon energy and the energy difference between the intermediate state |r 〉 and the initial state i〉. We only consider the first order Franck–Condon (FC) contribution to the RR signals in this work, since the higher order Herzberg-Teller terms only contribute slightly for strongly allowed electronic transitions [29–32]. The vibrational linewidth Γr = 10 cm−1 is used for the intermediate vibronic states. We aimed to identify the different Al(III)-peptide binding complexes by their RR characteristics that are correlated to the binding structures. To examine the excitation dependent vibronic effects, we constructed simple molecular models to capture the geometric configurations and the local chemical environments of the binding complexes according to previous calculations [17]. The two model structures corresponding to the intermediate binding complex and the five-membered ring, as well as a model peptide HCO–Ala–NH2 served as a reference for a typical peptide chain, are depicted in Fig. 1. For clarity, we named these complexes as complex I, complex II, and Ala, respectively. In addition to the peptide segment, we also placed a hydrated Al(III) ion near the peptide. The hydrate aluminum ion has the formula [Al(OH)(H2 O)4]2 + that widely exists in biological systems [33]. During the Al(III) induced protein denaturation, the hydrated Al(III) ion firstly interacts with the peptide carbonyl oxygen atom, and forms complex I. In the meantime, one water molecule initially coordinated to the Al(III) center is released, results in a lower coordinate number of 4 as shown in Fig. 1(b). The Al(III) ion in complex I can further bond to the neighboring amide nitrogen atom N1 to form complex II (see Fig. 1(c)). Here, the hydrogen atom H1 initially bound to N1 is substituted by the Al ion, together with the released water molecule initially bound to the Al(III) center, in the form of hydrate proton [H3 O]+. The formation of the ring structure in complex II would induce a dramatic change in the secondary structure, which would promote the aggregation of amyloid peptides. We used the Gaussian 09 package [34] with the (time-dependent) density functional theory (TD-DFT), the PBE0 hybrid functional [35–37] and the 6–311++G(d, p) basis set [38] in all the calculations. The geometries were optimized to minimize the ground state energy and forces at which excited state gradients and displacements were calculated [21]. The polarizable continuum model with conductor-like solvation (CPCM) [39,40] was used to perform the self-consistent reaction field (SCRF) calculations to simulate the aqueous environment. We performed natural transition orbital (NTO) [41] analysis for the electronic transitions. To correct the systematic error in the density functional frequency calculations, we scaled all the vibrational frequencies by a factor of 0.97 [42]. In the calculation of the UV-vis absorption spectra, we used the cumulant expression to bypass the
characterize the electronic and geometric structures of complex systems, thanks to its intrinsic selectivity upon electronic transitions and its sensitivity to the local chemical environment of the samples [7,19–26]. In RR measurements, electronic transitions with specific spatial or energetic localization characters can be selected by carefully tune the excitation wavelength. The resonant condition would enhance the scattering intensities by a factor greater than 106 [19]. Vibrational modes strongly coupled to the selected electronic transitions can then be detected by measuring the scattered light. It has been shown that peptide or side-chain vibrations can be selectively enhanced by tuning the excitation wavelength resonant with the interested electronic transitions, enabling the characterization of protein secondary structures [27]. In addition, unlike infrared spectra, the O–H bending mode of water is not Raman active, which will not overlap with typical peptide Raman bands, making RR suitable for biological systems in aqueous environment. In this paper, we performed ab initio calculations for the Resonance Raman spectra of the previously proposed complexes appeared during the Al(III)-peptide binding, and illustrates that the RR signals contain detailed structural information of these complexes. Distinct features in the RR spectra can be directly related to the vibronic excitations of each binding complex. 2. Computational protocol The resonance Raman process involves an electronic (and probably a vibronic) excitation from the ground electronic state followed by an emission back to a vibrational state in the ground electronic manifold. The difference in the initial and the final states produces the inelastic character of the Raman scattering. The differential Raman scattering cross section is given by [28], 2 Ifi dσ π 2 ∼3 ν0 ν fi αfi fi (T ) = = 2∼ dΩ I0 ∊0
(1)
where I0 and Ifi are the excitation and scattered wave intensities of the Raman process with the initial state i〉 and the final state |f 〉. ∊0 is the νfi are the excitation and scattered frevacuum permittivity, ∼ ν0 and ∼ quencies (in wavenumbers), respectively. fi (T ) is the occupation probability of the state i〉 at the temperature T, and αfi is the transition polarizability. At resonance, the transition polarizability can be written as,
αfi =
1 ℏ
∑ r
〈f μ r 〉〈r μ i〉 . ωri−ω1−iΓr
(2) 2
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Fig. 2. Vibrational resolved UV-vis absorption spectra of Ala (a), Complex I (b) and Complex II (c). The total absorption spectra are plotted in black. Electronic excitations with significant contributions labeled by εiS , which denotes the i-th electronic transition in system S, are also provided.
absorption spectrum, and ε5A contributes the most significant feature around 60,000 cm−1. The NTOs of the electronic excitations correspond to the four strongest excitations are depicted in Fig. 3(a). It is obvious that the absorption of Ala resembles the typical peptide UV-vis patterns, where the absorption peaks in the deep UV region originate from the peptide n-π∗ and π-π∗ electronic transitions [22]. This spectrum can be used as a reference to select appropriate excitation wavelengths for the RR measurements of complex I and II in the following. As shown in Fig. 2(b), four excitations contribute significantly to the total UV-vis spectrum of complex I. Compared to the absorption of Ala, ε7I can be ascribed to the peptide transition, which possesses similar excitation wavelengths of the strongest feature of Ala (Fig. 1(a)). The
summation over infinite terms [23,43], where the electronic linewidth was taken to be 100 cm−1. 3. Results and discussion 3.1. UV-vis absorption We first examined the UV-vis absorption of the complexes to check the possible excitation wavelengths for RR characterization. For clarity, we denote the i-th electronic transition of the system S as εiS . The vibration resolved UV absorption spectra of Ala are shown in Fig. 2(a). Four excitations contribute significantly to the total UV-vis
Fig. 3. The spatial distribution of NTOs of Ala (a), Complex I (b) and Complex II (c). 3
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Fig. 4. 2DSRR spectra of Ala (a), Complex I (b) and Complex II (c). The horizontal and vertical axes represent the Raman shift and the excitation energy, respectively.
other pronounced features are the consequence of the existence of the hydrated Al(III) ion and its binding with the peptide carbonyl oxygen atom. There are three weaker absorption bands at the low-frequency (long-wavelength) side of the peptide transition: ε2I at 221.79 nm, ε3I at 209.62 nm, and ε5I at 180.99 nm. Combining with the NTO plots shown in Fig. 3(b), these newly appeared features can be ascribed to the amide-Al charge transfer transitions. In detail, during the ε2I transition, charge transfers from the distant peptide bond to the hydrated Al(III)carbonyl region; during the ε3I transition, charge transfers from the Albonded carbonyl and the nearby amide to the metal ion; and for the ε5I transition, charge transfers from the Al-peptide region to the two distant water groups. The charge transfer characteristics of the electronic transitions indicate that the hydrated Al(III) ion strongly interacts with the peptide backbone, which agrees well with previous results [17]. The excitation resolved UV-vis spectra of complex II are shown in Fig. 2(c). Different from the spectra of Ala and complex I, the feature around 60,000 cm−1 (ε7II ) is much narrower than those of the former two systems. It is the consequence of the formation of the Al-peptide five-membered ring. The electronic transitions are localized on the peptide bonds in the former two systems, but is perturbed by the Al(III) contained ring structure. The corresponding NTO plot in Fig. 3(c) demonstrates that this excitation is localized at the ring structure. This localization eliminates the high-frequency C–H or N–H stretching modes, and restricts high probable vibronic excitations to low-frequencies, results in the much narrower peak width. The other features are also originate from excitations involving the ring structure. For instance, the weak peak around 48,000 cm−1 (ε1II ) corresponds to a charge transfer from the Al–N bond to the Al–O bond; the ε5II transition has a slight charge transfer from the ring structure to the peptide back bone. Although the UV-vis absorption spectra of complexes I and II both have distinct features compared to the typical peptide absorption patterns, it is not sufficient to identify these complexes only by UV-vis measurements. The concentration of these complexes would be at the nanomolar level and in a peptide abundant environment, the signal-tonoise ratio of the UV-vis characteristics would be too low to detect. However, the distinctions in the excitation energies and transition characteristics provide the possibility to identify the correlation between the structures and vibronic signals by using resonance Raman.
(2DSRR) spectra of Ala and the binding complexes are shown in Fig. 4. The 2DSRR signals can be viewed as a two-variable function, with the Raman shift as one independent variable (horizontal axis) and the excitation energy as the other (vertical axis). By fixing the excitation energy, we obtain a horizontal slice represent the corresponding resonance or pre-resonance Raman spectrum. We selected a series of RR spectra and plotted them in Fig. 5, these slices are excited with lasers resonant with the typical electronic transitions discussed above. The 2DSRR patterns can also be sliced in the vertical direction, where the Raman shift is fixed. In this manner, we get the Raman excitation profile corresponding to a specific vibration mode. Another interesting pattern in the 2DSRR spectra is the peaks along the diagonal (tilted to the top right) direction. These strong peaks have coordinates (ν , ε + ν )
3.2. Resonance Raman characteristics
Fig. 5. RR spectra with selected excitation energies of Ala (a), Complex I (b) and Complex II (c). The excitation energies are selected to be resonant to those of strong electronic transitions labeled by εiS .
The calculated two-dimensional spontaneous resonance Raman 4
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in the 2DSRR spectra, where ν is the Raman shift (horizontal variable) and ε is the electronic transition energy (vertical variable). These patterns can be ascribed to the resonance enhancement of a specific vibration mode by a 1 ← 0 vibronic excitation in the manifold of the electronic transition ε [23]. We should note that these peaks lie exactly on the diagonal direction is the result of the approximations we adopted. In the Raman calculations, we used the linearly coupled harmonic model [44,45] and neglected the Duschinsky rotations, hence the vibration modes are exactly the same for all the electronic states. By considering the variation of the curvatures of the electronic potential energy surfaces and the Duschinsky rotations, the vibration modes would be linearly combined, and the new frequencies would be slightly shifted. As a result, the tilted patterns would appear in the vicinity of the diagonal direction, and the overall 2DSRR pattern would not change significantly. The 2DSRR patterns of the Ala and the two binding complexes exhibit distinct features both in the Raman profiles and the RR spectra. These distinctions originate from the differences in the electronic excitations (Fig. 2), in the molecular vibrations, and in the coupling between them. All these information can be directly correlated to the geometric configurations of the complexes and the local chemical environments they reside in. We first examine the 2DSRR patterns vertically, i.e. the Raman profiles. The Raman profile of a vibration mode can be viewed as an electronic absorption dressed by the vibronic coupling between this vibration mode and the electronic excitations involved in. Therefore, the Raman profiles resemble the main features of the electronic spectra shown in Fig. 2. In Fig. 4(a), all the strong signals appear in the region with excitation energies higher than 58,000 cm−1, which correspond to the peptide absorption peaks in Fig. 2(a). There are also weaker features in the range 50,000–58,000 cm−1, which are the consequence of the coupling between the vibration modes and ε2A, ε3A , and ε4A . These transitions contribute to the lower-energy tail of the Ala main absorption peak. The 2DSRR spectrum of complex I shown in Fig. 4(b) presents a very different pattern compared to that of Ala. The features with excitation energies above 58,000 cm−1 are similar, with those of complex I slightly blue shifted, while the patterns below 58,000 cm−1 are totally different. The features with lower excitation energies are ascribed to the vibronic coupling with the charge transfer transitions, such as ε2I , ε3I , and ε5I . In Fig. 4(c), strong features appear in the excitation range above 54,000 cm−1. These features are the results of the high probable electronic transitions ε4II , ε5II , ε7II , and those with even higher excitation energies. Obviously, both the Al-O bonding in complex I and the formation of the ring structure in complex II brings considerable RR characteristics for chemical identification. We then discuss the 2DSRR features horizontally, in which case a series of electronic excitations were specified, and the horizontal slices represent the vibration mode dependent vibronic coupling with the particular electronic transitions. The resonant condition of RR measurements enforces that the RR intensity be proportional to the square of the transition dipole. This would amplify the difference in the magnitude of RR signals correspond to different electronic excitations. The RR spectra with selected excitation wavelengths are depicted in Fig. 5, where weaker signals were re-scaled for better visibility. Fig. 5(a) depicts the RR spectra excited with wavelengths resonant with the ε2A, ε3A , and ε4A transitions. All these spectra resemble the typical peptide RR features [46–49,22], i.e. the AmI bands at 1707 and 1685 cm−1, correspond to the carboxyl stretching modes at the N- and C-terminus, respectively; the AmII bands around 1494 cm−1; the AmIII modes around 1200 cm−1; and the Cα −H modes around 1380 cm−1. We also note that the C2–C3 stretching mode at 713 cm−1 has a much stronger relative intensity for ε5A than excited with ε2A and ε3A , as a result of the significant localization of the electron and the hole states at the C2–C3 bond in the ε5A transition (see Fig. 3(a)). Other notable RR features are listed in Table 1. The RR spectra of (Ala)2 provide a reference as the standard peptide RR features in this simulation.
Table 1 Raman active modes of Ala. All frequencies are wavenumbers. Frequency/cm−1
Description
1708 1685 1574 1495 1387 1245 1195 1113 713
AmI at the C-terminus AmI at the N-terminus N–H bending at the N-terminus AmII Cα –H bending AmIII of the N-terminus part AmIII of the C-terminus part C2–C4 stretching C2–C3 stretching combined with N2–H bending
Table 2 Raman active modes of Complex I. All frequencies are wavenumbers. Frequency/cm−1
Description
1691 1659 1501 1481 1371 1278 1224 1111 832
AmI at the C-terminus AmI at the N-terminus AmII at the C-terminus AmII at the N-terminus C1–H bending C2–H bending AmIII out-of-phase Al–O2 and O2–C3 stretching C3–C2 stretching
Three RR spectra of complex I resonant with ε2I , ε3I , and ε5I are presented in Fig. 5(b), and the corresponding vibration modes are listed in Table 2. The common feature of these spectra is the doublets appear at 1500 and 1480 cm−1, which are ascribed to the AmII mode near the C- and N-terminus, respectively. The latter mode is red-shifted due to the increasing of effective mass of the oscillator upon Al(III) bonding. Another characteristic feature is the out-of-phase combination of Al–O2 and C3–O2 stretching modes at 1111 cm−1. The AmI bands also splits into two peaks at 1691 and 1659 cm−1, as a result of the fact that the Nterminus carbonyl is bonded to the Al(III). Since the electron state of ε2I is localized at the hydrated Al(III) and the N-terminus of the peptide, the C-terminus AmI band is much weaker than those of the other excitations. The RR spectra of complex II resonant with ε1II , ε5II and ε7II are shown in Fig. 5(c). We note that the ε1II excited RR spectrum is weaker due to the weak electronic transition. As the result of the formation of the ring structure, which involves the Al(III) ion and the N-terminus carbonyl group, the AmI band corresponds to this carbonyl is significantly hindered. The common feature of the selected RR spectra is the triplet at 1255, 1284, and 1310 cm−1, correspond to the Cα −H mode decorated by the ring distortions. The C2–C3 stretching mode fixed by the ring structure would also be characteristic if the excitation laser is tuned to be resonant with excitations consist considerable contributions from the C2–C3 bond (Fig. 5(c)). For instance, part of the hole state of the ε1II transition is localized on the C2–C3 bond, leading to a sharp peak at 1466 cm−1. The formation of the ring structure also provide another feature in the range 1050–1130 cm−1, coming from the in-plane distortion modes of the Al-peptide ring.Table 3. Both the RR characteristics of the complexes I and II have distinct features compared to those of the Ala, which represents the typical peptide signals in this work. It is even more important that the characteristic RR features of complexes, such as the combined Al–O2 and C3–O2 stretching of the complex I and the ring-distortion related triplet of the complex II, do not overlap with any peptide Raman bands. Considering the resonance enhancement of the RR signals, these RR features would be detectable even in a peptide abundant environment, making RR suitable to chemically identify these complexes.
5
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Table 3 Raman active modes of Complex II. All frequencies are wavenumbers. Frequency/cm−1
Description
1681 1656 1548 1467 1398 1310 1285 1255 1128 1099, 1055 944 763
AmI at the C-terminus C3–N2 stretching coupled with N2–H bending AmI at the N-terminus (in ring) C2–C3 stretching (in ring) C1–H bending Cα 2–H bending coupled with C1–N1 stretching Cα 2–H bending coupled with Al–N1 stretching Cα 2–H bending coupled with C3–O2 stretching N1–Al stretching coupled with N1–C2 stretching Al-peptide ring in-plane torsion Al–N1 stretching Al-peptide ring out-of-plane torsion
[3] [4] [5] [6] [7] [8] [9] [10] [11] [12] [13] [14] [15] [16] [17]
4. Conclusions
[18] [19]
We calculated the vibrational resolved UV-vis absorption and the RR spectra of the Al(III)-peptide binding complexes by using simple molecular models. The complexes I and II are proposed to be crucial in the binding dynamics between Al(III) and peptide backbones, which would lead to the aggregation of amyloid peptides. The detailed vibronic patterns are discussed and their correlation to the geometric and electronic structures, as well as the local chemical environments are illustrated. Using the HCO–Ala–NH2 model as a reference to typical peptides, each complex has characteristic vibronic features and would be detectable with the help of the resonant enhancement in RR measurements. RR is a powerful tool for the chemical identification of samples at low concentrations usually encountered in the study of life sciences. Complimentary to conventional NMR, EPR, and XRD measurements, together these techniques can be used to reveal the microscopic dynamical details of the Al(III)-peptide binding and induced aggregation.
[20] [21] [22] [23] [24] [25] [26] [27] [28] [29] [30] [31] [32] [33] [34]
[35] [36] [37] [38] [39] [40] [41] [42] [43]
Acknowledgments We acknowledge the financial support from the National Natural Science Foundation of China (NSFC, Grant No. 21773309, 21573129, and 21403300), the China Postdoctoral Science Foundation (Grant No. 2014M560587), and High-level Science Foundation of Qingdao Agricultural University (663/1114351). Part of the calculations were carried out at the National Supercomputing Center in Shanghai.
[44] [45] [46] [47] [48]
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