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Mutation of the Phe20 Residue in Alzheimer’s Amyloid β-Peptide Might Decrease Its Toxicity Due to Disruption of the Met35-Cupric Site Electron Transfer Pathway Dariusz Pogocki* Institute of Nuclear Chemistry and Technology, Dorodna 16, 03-195 Warsaw, Poland Received September 16, 2003
It has been proposed that the Met residue in the C-terminal domain of the Alzheimer’s disease β-amyloid peptide (βA) serves as a source of electrons for the Cu(II)-catalyzed reduction of molecular oxygen to hydrogen peroxide. Mechanistically, this process would require the long distance electron transfer from the thioether sulfur to the peptide-bound copper. Therefore, the electron transfer pathways between the Met35 sulfur atom and the cupric site in the N terminus of βA congeners have been analyzed applying semiclassical models of long distance electron transfer. Simulations performed for several βA conformers collected along the 6 ns Langevin Dynamics trajectories suggest that the presence of the Phe20 residue in the peptide is required for feasibility of the electron transfer. Thus, I would like to propose the mutation Phe20Ala in βA as a potential way to reduce its neurotoxicity.
Introduction The neurotoxicity of β-amyloid peptide (βA), partially responsible for Alzheimer’s disease, is caused by the formation of free radicals and/or reactive oxygen species leading to lipid and protein oxidation (1-6). It has been suggested that the methionine residue (Met) in the C-terminal domain of βA serves as a source of electrons for the CuII-catalyzed reduction of molecular oxygen to hydrogen peroxide (7-14). The observed hydrogen peroxide may be formed in the presence of oxygen, in a Fenton-like cycle, which generates hydroxyl radicals (•OH) and superoxide radical anions (O2•-) (reactions 1-4):
O2 + CuI f CuII + O2•-
(1)
O2•- + O2•- + 2H+ f H2O2
(2)
O2•- + CuII f O2 + CuI
(3)
H2O2 + CuI f •OH + CuII + OH-
(4)
It has been subsequently discovered that His6, His13, His14, and Tyr10 amino acid residues may cooperatively bind cupric cations with high affinity in the full length βA1-42 (15, 16). However, on the basis of the reduction potentials of the copper site in βA (0.5-0.55 V vs Ag/ AgCl) and MetS/MetS•+ couple of free methionine (1.261.5 V vs Ag/AgCl) (7, 17), direct oxidation of Met35 by βAbound CuII (eq 5), which could deliver CuI for the initiation of Fenton cycle, appears thermodynamically quite unfavorable.
MetS + βA(CuII) h MetS•+ + βA(CuI)
(5)
* To whom correspondence should be addressed. Tel: +48228113021. Fax: +4822-8111530. E-mail:
[email protected].
On the other hand, I have recently provided some experimental and theoretical evidence showing that equilibrium 5 can be partially shifted to the right-hand side, due to the complexation of Met radical cation (MetS•+) (18-20). Such complexation can occur due to the close contact of the Met sulfur with the neighboring amide oxygen in the R-helically arranged conformation (18, 19, 21). It may lower the reduction potential of Met up to ca. 0.5 V as electrochemical oxidation of dialkyl sulfides showed lower peak potentials when appended with a neighboring carboxylate or alcohol group (22, 23). Just recently, Kadlcik et al. (24) have reported that they were able to oxidize Met35 in βA1-40 by azide radicals (N3•) of the reduction potential E°(N3•/N3-) ≈ 1.33 V vs NHE (25). It suggests that the reduction potential of Met35 in βA is decreased by at least 0.2 mV as compared to that of free amino acid. Moreover, the oxidation of Met sulfide may be accelerated by other reactions, which may remove products from equilibrium 5, such as formation of CuII/superoxide complexes (26, 27) and/or deprotonation of MetS•+ (28). The latter reaction, practically irreversible, is relatively fast (k ≈ 2.5 × 105 s-1) (29). It could be additionally accelerated in brain fluids by the presence of various proton acceptors such as phosphates (28). Thus, it seems reasonable that Met35 sulfide may reduce the cupric site in βA via long-range electron transfer (ET). Furthermore, the extensive survey of ET proteins performed by Dutton and co-workers (30) suggests that in the donor-acceptor distance of 17-19 Å, observed in R-helically rich βA conformations (31), the ET should not be considered as impossible.
Simulation Results and Discussion In this paper, the ET pathways between the Met35 sulfur atom and the cupric site in βA congeners have been analyzed. Moreover, it has been assumed that only R-helically organized conformers of βA are redox active because of the neighboring group-assisted oxidation of Met35 sulfide (11, 12, 14, 18, 21, 32). Therefore, the initial
10.1021/tx030044w CCC: $27.50 © 2004 American Chemical Society Published on Web 02/05/2004
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structure of the peptide was derived from the published solution structure of βA1-42 (31). The βA conformers were collected along the 6 ns Langevin Dynamics (LD) trajectory (33), obtained in the following time intervals: 0.02, 0.100, 1, and 5 ns every 0.9, 4.5, 45, and 220 ps, respectively. The LD simulations were performed in a single molecule configuration in conditions (a collision frequency and continuum of an appropriate dielectric permittivity) that mimic the properties of water and lipid phases. Such simplification of the method consists on one hand of an arbitrary choice of initial conformation and on the other an application of LD for examination of the peptide conformational space; therefore, it is not free of limits. One should be aware that the method does not cover the entire conformational space of the peptide. Nevertheless, the method should allow adequate probing of the local conformational space around the R-helical peptide local minimum defined in the NMR spectroscopy experiment (31). The PATHWAYS (34, 35) and the Dutton’s (30, 36) semiclassical and phenomenological models of long distance ET have been applied for each conformer. (Further details of the simulation procedure as well as some ET theory basics are presented in the Appendix). This work does not attempt to resolve the question of the amplitude of ∆G° in the particular ET process. Two “∆G°-independent” parameters characterizing an ET pathway will be used for comparison of the peptide congeners: vmax DA , the tunneling matrix element for the fastest single ET pathway (originated from the PATHWAYS model), and kmax et , the highest exergonic electron tunneling rate constant calculated using Dutton’s model with ∆G° equal to the reorganization energy λ. However, concerning the values of λ equal to ca. 0.8 and 1.5 eV obtained by the finite difference Poisson-Boltzmann model (FDPB) calculations for the lipid and water phase, respectively, and assuming ∆G° ≈ 0.5 eV [based on data provided by Kadlcik et al. (24)], I may calculate more realistic endergonic ET rate constants, multiplying kmax et by 2.7 × 10-9 and 4 × 10-11 for the lipid and water phase, , will be shown respectively, which, named as ken,0.5eV et . simultaneously with kmax et Both ET models utilized are formally different; however, they have chosen the same family of βA conformers of the fastest ET pathway. A typical example of the ET suitable βA1-42 conformation obtained in a water phase simulation is shown in Figure 1A. In this conformer, ET occurs over the distance of ca. 18.2 Å, involving the following amino acid residues: Met35, Phe20, Lys16, Gln15, and His14. Remarkably, the through space jump between residues 35 and 20 and participation of the hydrogen bond between 20 and 16 peptide bonds in the ET pathway are suggested. This particular configuration secures the Dutton’s model protein packing density F of ca. 0.7 (in principle, F can range from 1, corresponding to a fully packed medium, to a value of 0, corresponding to the interstitial space in the protein structure outside the united van der Waals atomic radii.) Thus, kmax is equal et -7 -1 to ca. 2.8 × 102 s-1 (ken,0.5eV ≈ 7.6 × 10 s ) and vmax et DA to -7 ca. 10 . Importantly, all effective ET pathways observed in βA conformers involve as a first step a through space electron jump between Met35 and Phe20 residues. Therefore, one may assume that the Phe20 residue plays an important role in ET pathway. Most probably, the aromatic side chain of Phe20 serves here as a shortcut
Pogocki
Figure 1. ET pathways in selected conformers of βA1-42 (A) and βA1-42(Phe20Ala) (B). The color balls represent atoms involved in the ET pathway. The rainbow colors (from red to dark green) represent electron tunneling coupling between donor and acceptor, which decrease from high to low relative values.
between two R-helical sections of βA (residues 15-24 and 28-36) over the kink containing 25-27 residues (3739). To support this hypothesis, I have repeated the procedure for Phe20Ala-mutated βA1-42. Indeed, for the βA1-42(Phe20Ala) congener, I did not find conformers with kmax higher than 10-2 s-1 (ken,0.5eV ≈ 3 × 10-11 s-1). An et et example of one of the ET “suitable” conformers of βA142(Phe20Ala) is shown in Figure 1B. In the conformer shown here, an electron has to travel over the distance of ca. 25.4 Å through the following amino acid residues: Met35, Lys28, Asn27, Glu22, Val18, and His14. The pathway requires at least three through space jumps (between 35 and 28, 27 and 22, and 22 and 18 residues). This is reflected in a lower electronic coupling between donor and acceptor residues, which is qualitatively illustrated in Figure 1. However, despite the high packing density F (ca. 0.7), kmax reaches only ca. 7 × 10-3 s-1 (ken,0.5eV ca. et et -11 -1 -10 1.9 × 10 s and vmax ) due to the large DA ca. 10 donor-acceptor distance (saturation of the conformer by explicit water molecules does not change significantly max neither the kmax et nor the vDA values). On the other hand, comparison of the ET abilities in βA1-42 and βA1-42(Phe20Ala), obtained for their conformers in conditions mimicking a lipid phase environment, is very informative. Here, significant differences between βA1-42 and βA1-42(Phe20Ala) are not observed. The kmax values for et both congeners are ca. 10-2 s-1 (ken,0.5eV ca. 4 × 10-13 s-1 et -8 and vmax DA ca. 10 ), with F in the range of 0.56-0.6. The calculated 21.2-22 Å donor-acceptor distance is much larger as compared to a donor-acceptor distance in water phase conformers (ca. 18 Å, vide supra) and seems to be solely responsible for significantly lower rate constants.
Phe20 Residue in Alzheimer’s Amyloid β-Peptide
In a lipid phase for βA1-42 conformers, eight amino acid residues (Met35, Val24, Phe20, Ala21, Leu17, Lys16, Gln15, and His14) are usually on the ET pathway. On the other hand, for βA1-42(Phe20Ala), seven residues (Met35, Gly25, Val24, Asp23, Phe19, Gln15, and His14) are involved in the transfer. Comparison of data obtained in water and lipid phases suggests that observed differences in predicted ET rates between βA congeners are mainly caused by the conformation-related differences in a donor-acceptor distance due to hydrophobic effects. I believe that hydrophobic attraction between Phe20 and Met35 residues plays an important role in the stabilization of the secondary structure of the native peptide in water. Generally, such attraction decreases repulsion between two R-helical parts of the peptide in contradiction to the Ala20 mutant (see Figure 1). This has resulted in an increased exposure of the hydrophilic amino acids of the kink (Ser26 and Asn27) to bulk water and in a decrease of the ET donoracceptor distance, whereas in the lipid phase the hydrophobic attraction plays less important role. Hence, the Phe20 and Met35 residues (and R-helices as well) are separated by a longer distance. Considering the computational data gathered so far, I feel encouraged to suggest for consideration to the bioscience community that the Phe20Ala mutation of βA could potentially decrease the peptide toxicity in vitro. I assume that such mutation will not change significantly the helicity of the peptide; however, it should decrease the efficiency of free radicals production, additionally justifying the aforementioned hypothesis of spontaneous reduction of cupric cation by βA. I am positive that lower oxidative stress and neurotoxicity measures with β-peptide 1-42 with Phe20 substituted by Ala could be determined if my hypothesis has merit.
Acknowledgment. This work was supported in part by the European Community’s Human Potential Program under contract HPRP-CT-2002-00186 (SULFRAD). Parts of the computations were performed employing the computing resources of the Interdisciplinary Center for Mathematical and Computational Modeling at the University of Warsaw, Poland (ICM G24-13).
Appendix Molecular Simulations and Computational Details. 1. Structures of Peptides. Initial structures of the “apo”-peptide were derived from the published solution structure of βA1-42. It was obtained by distance geometry calculations employing NMR-derived NOE restraints (31). Because of the lack of a specific structure of the “holo”-peptide, its structure was assembled based on its apo-structue (31) and the publicly proposed structure of the Cu2+ coordination site (9) and then equilibrated. 2. Computational Details. All simulations were performed in the extended atom model. As a potential energy function, I employed the CHARMM potential (40, 41) in its HyperChem implementation (42). To simulate the presence of water solvent, a scale factor (dielectric permittivity) equal to 80, which screened the chargecharge interactions, was utilized. Such a simplification has been shown to give results that quantitatively agree with solvent simulations (43). The presence of a lipid environment was mimicked by dielectric permittivity
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equal to 3, which is comparable to experimental values for liquid fatty acids and esters (44). The modeling of peptides was performed with the default Bio85+ set of parameters that is an equivalent of the PARAM19 parameter set (45). However, the parameters for a copper cation were adopted from the Quanta 3.3 parameters set (46). The conformational changes of the peptides were followed along the LD (33, 47-50) simulation trajectory, in a single molecule configuration, with a collision frequency (γ) for all heavy atoms equal to ca. 50 ps-1 in water and ca. 1000 ps-1 in the lipid environment; these were set proportional to the respective viscosity of water (ca. 1 cP) and of a lipid bilayer (ca. 200 cP) required to fit molecular dynamics and experimental data (47, 51). The dielectric properties of water solvent were mimicked utilizing a scale factor () equal to 80, which screened the charge-charge interactions. Similarly, the presence of a lipid environment was mimicked by a value equal to 3, which is comparable to experimental values for liquid fatty acids and esters (44). The free LD simulations were performed with the 2 fs time step and 20 ps to 6 ns propagation time, preceded by 12 ps of heating from 0 to 300 K and 18 ps of equilibration. For practical purposes (1 ns of dynamics required ca. 10 CPU hours), the LD propagation time was limited to 6 ns, a time at least 1 order of magnitude longer than the average time required for the rotation of side chains on the surface of proteins [typically 10-11-10-10 s (52)]. For the force field calculations, the HyperChem PC molecular modeling package (version 7.1) was used (42), which integrates the Langevin equation of motion using the method of Allen and Tildesley (53). All selected βA conformations were analyzed using the HARLEM molecular modeling package (54), which implemented the PATHWAYS (34, 35) and the Dutton (30, 36) models of the ET pathway analysis, and the FDPB for the estimation of ET reorganization energies (55). For the purpose of the ET pathways analysis, the electron acceptor center included the copper cation together with imidazole and phenyl rings of His6, His13, His14, and Tyr10 amino acid residues. Parameters used in the FDPB calculations were as follows: grid dimensions were 65 × 65 × 65. The scale was adjusted so that the molecule filled 60% of the box. To mimic the physiological fluid conditions, dielectric constants of 4 and 80 (representing the contribution from nuclear reorientation and electronic polarizability) were assigned to the peptide and solvent, respectively, and an ionic strength of 0.16 M (representing the contribution of ion reorganization) was assigned to the solvent. The ion exclusion radius was set as 2 Å, and the solvent probe radius was set as 1.4 Å. The lipid phase calculations were performed with dielectric constants of 4 and 3 assigned to the peptide and solvent, and the ionic strength was set to zero. Basics of the Applied Long Distance ET Models. In the following paper, I apply two models in order to calculate the ET rates. In the first model, the pathways model, Beratan and Onuchic, provides a semiempirical model to calculate the electronic coupling between redox centers (34). The second model, the phenomenological model of Dutton and co-workers, relates the rate of ET to the distance between redox centers (36). In the pathways model, the rate constant of ET (ket) (the reaction in eq 5) is proportional to the square of the tunneling matrix element (VDA) between methionine
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sulfur as a donor (D) and the cupric site as an acceptor (A) and to the density of vibrational states weighed by their Franc-Condon factors (the exponent) (eq A1).
[
ket ) (4π2/h)|VDA|2x4πλkBT exp -
]
(λ + ∆G°)2 4λkBT
(A1)
The symbols λ and ∆G° represent a reorganization energy and Gibbs free energy of the reaction, respectively (56). An electron tunneling path is a combination of interacting covalent bonds, hydrogen bonds, and van der Waals contacts (interaction through space) that link the donor and the acceptor. The respective decay parameters for attenuation of electronic coupling via these bonds and contacts are the unitless quantities C, H, and S, defined in eq sA
) R exp[-β(r - req)]
(A2)
and calculated with the standard parameters R, β, and req; r is the distance between the interacting atoms. For the sake of simplicity, in the paper, I applied the original C, H, and S of 0.6, 1.7, and 1.7, respectively. The tunneling matrix element for a single path (vDA) is proportional to the relative coupling according to eq A3. NC
vDA ∝
NS
NH
C(i) ∏ S(j) ∏ H(k) ∏ i)1 j)1 i)k
(A3)
The total tunneling matrix element (VDA) in eq s1 includes the elements vDA for various possible paths. To the best of our knowledge, the difficult problem of interaction among paths, i.e., the relation between VDA and vDA, has not yet been fully solved. Because the parameters in eq A3 are ultimately based on experimental results, these parameters implicitly account for the multiplicity of paths. However, one or few paths usually dominate the overall coupling. The Dutton model predicts that ET rates (ket) will vary exponentially with the distance (RDA) separating the donor and the acceptor and with the packing density of the protein (F) in the region between redox sites. Equation A4 gives an empirical expression for an exergonic electron tunneling rate kex et .
log10kex et ) 13 - (1.2 - 0.8F)(RDA - 3.6) 3.1(λ + ∆G°)2/λ (A4) Whereas eq A5 estimates the rate of endergonic tunneling steps by using eq A4 for the opposite exergonic step and dividing by the temperature-dependent Boltzmann factor or equilibrium constant (10∆G/0.06 at room temperature).
log10ken et ) 13 - (1.2 - 0.8F)(RDA - 3.6) 3.1(λ - ∆G°)2/λ - ∆G/0.06 (A5) The free energy ∆G° and the reorganization energy λ are expressed in eV. Importantly, in the Dutton model, the dependence of the rate on the protein structure arises in eqs A4 and A5 through the parameter F, which represents the
packing density of the protein between the redox centers and is not very sensitive to the atomic details of the structure.
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