pubs.acs.org/Langmuir © 2009 American Chemical Society
Aggregation of Amyloidogenic Peptides near Hydrophobic and Hydrophilic Surfaces Ivan Brovchenko,* Gurpreet Singh, and Roland Winter Physical Chemistry, Dortmund University of Technology, Otto-Hahn-Strasse 6, 44221 Dortmund, Germany Received February 18, 2009. Revised Manuscript Received March 31, 2009 The general effect of surface hydrophobicity/hydrophilicity on the aggregation of peptides is studied by simulations of oversaturated aqueous solutions of hydrophobic and hydrophilic amyloidogenic peptides. Peptide aggregation was studied in bulk solution, in solutions confined between hydrophobic boundaries (smooth planar paraffin-like surfaces and liquid-vapor interfaces) and in solutions confined between hydrophilic surfaces (smooth planar silica-like surfaces). Aggregation of hydrophobic peptides strongly enhances due to the confinement between hydrophobic surfaces with all peptides adsorbed at the boundaries and aligned predominantly parallel to them. In the other three cases considered, the peptides are repelled from the walls and do not reveal orientational ordering with respect to the surface. The degree of peptide aggregation in these cases is only slightly affected by the confinement (it is enhanced for hydrophobic peptides and decreased for hydrophilic peptides). Our results show that even a single environmental factor such as water-mediated peptide-surface interaction has a drastic effect on the degree and character of peptide aggregation. A wide diversity of possible scenarios can be expected when specific peptide-surface interactions are additionally taken into account.
Introduction In recent years, it has become evident that misfolded proteins and peptides are of enormous biophysical, medical and pharmaceutical importance. On the one hand, they can aggregate into fully ordered amyloid fibrils consisting of cross β-sheet structures. These fibrils and their precursor oligomeric structures have been studied extensively in the last years due to their central role in diseases such as Alzheimer’s, Parkinson’s, and type II diabetes mellitus.1 Remarkably, nonpathogenic amyloid has been found in a diverse range of organisms: from bacteria to mammals as well. It is therefore particularly important to understand the underlying physical and chemical principles which trigger, control or prevent amyloid formation. The main regularities of the physical aggregation of interacting objects are described by the laws of statistical physics. The phase transition is an important guiding line in the description of physical aggregation. With approaching the phase transition (by varying the concentration, temperature, etc.), the aggregation of the minor component is facilitated and, at the phase transition, an infinite (macroscopic) aggregate is formed. In the case of aqueous solutions, the aggregation (clustering) of both water and solute molecules depends on the proximity to the demixing transition, where separation of the aqueous solution into a water-rich and an organic-rich (aggregate) phase takes place. For example, the demixing transition of the aqueous solution of amyloidogenic peptides results in its separation into amyloid fibrils (organic-rich phase) and an aqueous solution exhibiting an extremely low critical peptide concentration (water-rich phase).2,3 The aggregation phenomena of biomolecules in aqueous environment can be complicated by several factors. Due to hysteresis phenomena, the formation of an equilibrated
aggregated (organic-rich) phase may take extremely long times (years in the case of the highly insoluble amyloidogenic peptides, whose solubility limit is below the picomolar range2,4). Also, the finite size of a system prevents formation of a condensed phase in oversaturated conditions.5 Therefore, aggregation of highly insoluble peptides can be suppressed in small volumes (for example, in biological cells and in their compartments).3 Further complications may arise from the irreversible chemical reactions in the process of aggregation. The presence of extended surfaces is another important factor that affects peptide aggregation. Clearly, the interplay of all theses factors as well as varying thermodynamic conditions complicates the possibility to characterize and predict the process of peptide aggregation. To understand its main regularities, it is thus reasonable to reveal separately the key factors affecting aggregation. In the present paper, we consider the effect of various surfaces on the aggregation of peptides in liquid water using molecular dynamic simulations. Due to the presence of a surface, the peptide concentration as well as any other system property becomes local, that is, dependent on the distance from the surface. Clearly, the adsorption of peptides on a surface affects their aggregation behavior. If the peptide-surface attraction is strong enough, a surface phase transition (condensation of one or several condensed peptide layers at the surface) becomes possible. This transition occurs at some peptide concentration below the solubility limit of peptides in bulk liquid water. At higher peptide concentrations, the formation of an organic-rich phase (macroscopic amorphous or ordered peptide aggregates) becomes possible also in the bulk. However, within some range of peptide concentrations, the system is metastable with respect to the bulk demixing transition, but is unstable with respect to the surface phase transitions. Hence, the condensation of peptide layers on surfaces exhibiting
*Corresponding author. E-mail:
[email protected]. (1) Chiti, F.; Dobson, C. M. Annu. Rev. Biochem. 2006, 75, 333–366. (2) Jarrett, J. T.; Lansbury, P. T. Cell. 1993, 73, 1055–1058. (3) Singh, G.; Brovchenko, I.; Oleinikova, A.; Winter, R. Biophys. J. 2008, 95, 3208–3221.
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(4) Hortschansky, P.; Schroeckh, V.; Christopeit, T.; Zandomeneghi, G.; :: Fandrich, M. Protein Sci. 2005, 14, 1753–1759. (5) Binder, K. Eur. Phys. J. B 2008, 64, 307–314.
Published on Web 04/27/2009
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strong attractive interaction with peptides (regardless of the origin of this interaction) may be the key mechanism of peptide aggregation in a wide concentration range. The adsorption of peptides on a surface affects not only the degree of peptide aggregation, but may also change the structure of the peptide aggregate. The two-dimensionality of the surface should provide orientational ordering of the peptides as well as a preferential formation of two-dimensional aggregate. These effects are expected to be dominant when the surface phase transitions of the peptides occur on strongly attractive surfaces. Another important factor of the presence of a surface is its effect on the conformation of the single peptides, which, in turn, may affect both the degree of aggregation and the structure of the aggregate.6-8 Due to such multifaceted effect of a surface on peptide aggregation, it is useful to analyze various aspects of these surface effects separately. One key parameter is the effective strength of the peptide-surface interaction. In aqueous solution, this effective strength is determined by the relative strengths of the peptide-surface and water-surface interactions. The direct interaction between peptides and biological surfaces includes contributions from Coulombic interactions, dispersion interactions, and hydrogen bonding. The presence of a solvent (water) causes appearance of an additional, solvent-induced interaction between the peptide and the surface, which crucially depends on the strengths of the water-surface and water-water interactions. This solvent-induced interaction appears as an attraction between the hydrophobic parts of peptides and a hydrophobic surface, and as a repulsion between the hydrophilic parts of peptides and a hydrophilic surface. This interaction originates from the tendency of hydrophobic (hydrophilic) particles or surfaces to stay dehydrated (hydrated).9 Experimental studies have shown that the degree of peptide and protein aggregation as well as the structure of their aggregates change near surfaces and strongly depend on the surface properties.6-8,10-18 Hen egg white lysozyme is completely soluble in liquid water but forms macroscopic aggregates enriched in intermolecular β-sheets at a surface, whose hydrophobicity, governing the strength of the water-mediated protein-surface interaction, exceeds some value.13 The existence of a threshold value of the surface hydrophobicity necessary for the formation of the aggregated phase as well as the thickness of the adsorbed protein film (about 2-3 protein monolayers) indicates existence of a first-order surface phase transition of the lysozyme molecules at hydrophobic surfaces. Generally, amyloidogenic peptides are highly insoluble in water. Due to the long lag times of the bulk aggregation, peptide aggregates can appear at surfaces before their formation starts in (6) Matsuzaki, K.; Horikiri, C. Biochemistry 1999, 38, 4137–4142. (7) Giacomelli, C. E.; Norde, W. Biomacromolecules 2003, 4, 1719–1726. (8) Lopes, D.; Meister, A.; Gohlke, A.; Hauser, A.; Blume, A.; Winter, R. Biophys. J. 2007, 93, 3132–3141. (9) van Oss, C. J. J. Mol. Recogn. 2003, 16, 177–190. :: (10) Terzi, E.; Holzemann, G.; Seelig, J. J. Mol. Biol. 1995, 252, 633–642. (11) Kowalewski, T.; Holtzman, D. M. Proc. Natl. Acad. Sci. U.S.A. 1999, 96, 3688–3693. :: (12) Schladitz, C.; Vieira, E. P.; Hermel, H.; Mohwald, H. Biophys. J. 1999, 77, 3305–3310. (13) Sethuraman, A.; Belfort, G. Biophys. J. 2005, 88, 1322–1333. (14) Giacomelli, C. E.; Norde, W. Macromol. Biosci. 2005, 5, 401–407. (15) McMasters, M. J.; Hammer, R. P.; McCarley, R. L. Langmuir 2005, 21, 4464–4470. :: :: (16) Rocha, S.; Krastev, R.; Thunemann, A. F.; Pereira, M. C.; Mohwald, H.; Brezesinski, G. ChemPhysChem 2005, 6, 2527–2534. :: (17) Maltseva, E.; Kerth, A.; Blume, A.; Mohwald, H.; Brezesinski, G. ChemBioChem 2005, 6, 1817–1824. (18) Ku, S. H.; Park, C. B. Langmuir 2008, 24, 13822–13827. (19) Lepere, M.; Muenter, A.; Chevallard, C.; Guenoun, P.; Brezesinski, G. Colloids Surf. A: Physicochem. Eng. Asp. 2007, 303, 73–78.
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the bulk. The effect of surfaces on the aggregation reaction has been extensively studied for amyloid-β (Aβ) peptides.6,7,10-12,14-17,19 Aβ peptides exhibit strong adsorption at the intrinsically hydrophobic liquid-vapor interface.12,17,19 Adsorption of Aβ peptides was also observed on both hydrophilic6,11,14-16 and hydrophobic7,11,14-16 surfaces, as well as on both positively16 and negatively10 charged solid surfaces. On the other hand, desorption of Aβ peptides from some hydrophilic and negatively charged surfaces was also reported.16 On hydrophobic surfaces, Aβ peptides form a uniformed tightly packed layer12,16,19 or uniform, elongated sheets,11 whereas less ordered particulate aggregates appear at hydrophilic11 and positively charged16 surfaces. This points to a stronger interaction of Aβ peptides with hydrophobic surfaces. Variation of the properties of a membrane by changing the intramembrane ganglioside concentration evidence that some threshold concentration is required for the adsorption of Aβ peptides at such lipid surfaces.6 Fibrillation of prion peptides on solid surfaces strongly decreases upon heating.18 Both these features are consistent with the presence of surface phase transitions of amyloidogenic peptides on certain surfaces. Elucidation of the dominating forces in peptide adsorption in an experiment is complicated by the fact that it is difficult to vary some surface property (for example, its hydrophilicity), keeping all other properties of the surface (e.g., its structure, heterogeneity, charge) and peptide system constant. However, this can be achieved by computer simulations. Adsorption at membranes20,21 and at the liquid-vapor water interface22 has been studied by atomistic simulations for the case of a single amyloidogenic peptide, whereas their aggregation at surfaces has been studied on the level of a simplified model,23 only. In this paper, we present fully atomistic simulations of the aggregation of peptides in explicit water near model surfaces. We consider exclusively the effect of water-mediated peptide-surface interactions on peptide aggregation. In order to probe the range of possible scenarios, we use two kinds of highly insoluble amyloidogenic peptides (hydrophobic and hydrophilic) and two kinds of model smooth surfaces (hydrophobic and hydrophilic). The effects of the watersurface interaction on the degree of peptide aggregation and on the structure of the peptide aggregates formed are analyzed.
Systems and Methods We performed a series of computer simulation studies of oversaturated solutions of amyloidogenic peptides in liquid water. Two kinds of amyloidogenic peptides were used: the hydrophobic peptide NFGAIL, (residues 22-27 of the human islet amyloid polypeptide, molecular weight 633.75 Da), and the polar hydrophilic peptide GNNQQNY (residues 7-13 of the yeast prion Sup35, molecular weight 836.82 Da). The solutions were simulated in the bulk (with periodic boundary conditions applied in three dimensions) and in slit-like pores of 6 nm width (with periodic boundary conditions applied in two dimensions). Besides, the solution of hydrophobic peptides was simulated in an infinite liquid slab of about 6 nm width with two liquid-vapor interfaces. The use of such a wide pore makes the water properties in the pore center very close to the bulk ones. The aqueous solutions were represented by six peptides and about 62006700 water molecules. This corresponds to a weight concentration of peptides of about 3.1-3.3% for the solutions of the hydrophobic peptides and of about 4.0-4.3% for the solutions of the hydrophilic peptides. (20) Xu, Y.; Shen, J.; Luo, X.; Zhu, W.; Chen, K.; Ma, J.; Jiang, H. Proc. Natl. Acad. Sci. U.S.A. 2005, 102, 5403–5407. (21) Davis, C.; Berkowitz, M. Biophys. J. 2009, 96, 785–797. (22) Knecht, V.; Mohwald, H.; Lipowsky, R. J. Phys. Chem. B 2007, 111, 4161– 4170. (23) Friedman, R.; Pellarin, R.; Caflisch, A. J. Mol. Biol. 2009, 387, 407–415.
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Figure 1. Density profiles of liquid water in the hydrophobic and hydrophilic pores and in the slab of liquid water. Pore walls are located at -3 and +3 nm. The profiles near the pore walls and at the liquid-vapor interface are shown in an enlarged scale in the right panel. All atomic molecular dynamic simulations were carried out at T = 330 K with Gromacs software using the OPLS force field24 for the peptides and the SPCE model25 for the water molecules. The cutoff of 1.2 nm was used for intermolecular interactions and the PME method was used to treat long-range Coulombic interactions. The interaction of water molecules with the smooth pore walls was represented by a (9-3) Lennard-Jones potential. Two kinds of pore walls were considered: with a well-depth U0 of the water-wall potential equal to -0.30 kcal/mol, and with U0 = -3.90 kcal/mol. The strength of the water-surface interaction of these walls approximately corresponds to a strongly hydrophobic paraffin-like surface and to hydrophilic silica-like surfaces, respectively.26 The peptides did not interact with the walls. Simulation of the bulk aqueous solutions of the peptides were performed at P = 1 bar. In the case of the liquid slab simulations, the conditions of the liquid-vapor coexistence are provided by the presence of the vapor phase in the simulation box. Simulations of the aqueous solutions in pores were performed in the constantvolume ensemble. First, the pore was filled with liquid water and water molecules were added or deleted to adjust the water density in the pore center to the bulk density of SPCE water at the liquidvapor coexistence (about 0.985 g/cm3 at 330 K27). Afterward, six peptides were randomly inserted into the simulation box such that the peptides are at least 0.7 nm away from each other and 1.5 nm away from the surfaces, and water molecules overlapping with peptides were deleted. Such procedure ensures that the thermodynamic conditions of the solutions in the pores are close to those in the bulk. For each type of surface and peptide combination, five simulations with different initial velocities were carried out for the duration of 70 ns.
Results The density profiles of liquid water in the two types of pores considered and the density profile in the slab of liquid water are shown in Figure 1. These profiles were obtained from the local densities of the centers of water oxygens. Note, that the pore walls located at -3 and +3 nm correspond to the location of the centers of atoms forming the surface layer of the model solid. The data reveal a pronounced density depletion of liquid water near the (24) Jorgensen, W. L.; Tirado-Rives, J. J. Am. Chem. Soc. 1988, 110, 1657–1666. (25) Berendsen, H.; Grigera, J.; Straatsma, T. J. Phys. Chem. 1987, 91, 6269– 6271. (26) Werder, T.; Walther, J.; Jaffe, R.; Halicioglu, T.; Koumoutsakos, P. J. Phys. Chem. B 2003, 107, 1345–1352. (27) Guissani, Y.; Guillot, B. J. Chem. Phys. 1993, 98, 8221–8235. (28) Brovchenko, I.; Oleinikova, A. Interfacial and Confined Water; Elsevier: Amsterdam, 2008.
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Figure 2. Time dependence of the distribution of the centers of mass of hydrophobic peptides in the slab of aqueous solution (upper panel) and in the aqueous solution inside a hydrophobic pore (two independent simulation runs are shown in the middle and lower panels). The midpoints of the liquid-vapor interface are shown by dashed lines. The pore walls are indicated by horizontal black lines. The color scale on the right-hand side indicates changes of the peptide density.
hydrophobic surface caused by the domination of the effect of missing neighbors over the weakly attractive water-surface potential.28 The observed degree of the density depletion near the hydrophobic surface agrees with the available experimental data.29,30 The thickness of the liquid-vapor interface is larger than the thickness of the interface between liquid water and hydrophobic surface (see right panel in Figure 1). It is close to that obtained in other simulation studies31 and is slightly below the values obtained in the experiments (see ref 32) for data collection) due to the unavoidable suppression of the capillary waves in simulations. The two pronounced water layers near the hydrophilic surface are similar to those observed in numerous other simulation studies.28,33 The high value of the local density at the maximum of the first peak does not mean an enhancement of the water density in the first layer, but a strong localization of water molecules in a plane parallel to the surface. Strong orientational ordering of water molecules in the first surface layer becomes essentially weaker in the second layer and practically disappears starting from the third one.33 The time dependences of the probability distribution of the centers of mass of the peptides in the pores and in the slab of liquid water are depicted in Figures 2, 3. After random insertion of hydrophobic peptides in liquid water into the hydrophobic pore (29) Jensen, T. R.; Jensen, M. O.; Reitzel, N.; Balashev, K.; Peters, G. H.; Kjaer, K.; Bjornholm, T. Phys. Rev. Lett. 2003, 90, 086101. (30) Steitz, R.; Gutberlet, T.; Hauss, T.; Klosgen, B.; Krastev, R.; Schemmel, S.; Simonsen, A. C.; Findenegg, G. H. Langmuir 2003, 19, 2409–2418. (31) Taylor, R. S.; Dang, L. X.; Garrett, B. C. J. Phys. Chem. 1996, 100, 11720– 11725. (32) Caupin, F. Phys. Rev. E 2005, 71, 051605. (33) Brovchenko, I.; Oleinikova, A. Molecular organization of gases and liquids at solid surfaces. In Handbook of Theoretical and Computational Nanotechnology; Rieth, M., Schommers, W., Eds.; American Scientific Publishers: Stevenson Ranch, CA, 2006; Volume 9, Chapter 3, pp 109-206.
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or in the slab of liquid water, the equilibration of the system requires up to 30 ns. After equilibration, all peptides were adsorbed at the interfaces. Usually, the peptides are adsorbed on the two opposing interfaces, but sometimes all peptides are adsorbed at one of them, only. The situation is quite different in hydrophilic pores, where both hydrophilic and hydrophobic peptides (upper and lower panels in Figure 3, respectively) quickly (in a few ns) become localized in the center of the pore, and such scenario is also observed in the case of the hydrophilic peptides in the hydrophobic pore (middle panel in Figure 3). The density profiles of the peptides in the pores, calculated after the equilibration period of 30 ns and by taking into account all peptide atoms, are shown in Figures 4 and 5. The degree of peptide localization in the pore center is quite similar for both hydrophilic and hydrophobic peptides in the hydrophilic pore. The hydrophilic peptides, however, show a weaker localization in the center of the hydrophobic pore. An opposite behavior is observed for hydrophobic peptides in the hydrophobic pore or in a slab of liquid water, where in all simulation runs, the peptides are strongly adsorbed at the interfaces (Figure 5). The degree of peptide localization near interfaces essentially exceeds that in the pore center as can be seen from the comparison of the width of the density distributions shown in Figures 4 and 5. This can be additionally illustrated by the distribution of the centers of mass of the peptides. When the peptides are localized in the pore center, this distribution (not shown) practically coincides with that shown in Figure 4, whereas it is much narrower in the case of peptide localization near the interfaces (compare blue and red lines in Figure 5). The probability distribution of the angle R between the pore surface and the vector connecting two most distant peptide heavy atoms are shown in Figure 6. When the peptides are repelled from the pore walls and localized in the pore center, the orientations of
Figure 3. Time dependence of the distribution of the centers of mass of hydrophilic peptides in aqueous solution in the hydrophilic (upper panel) and hydrophobic (middle panel) pores and of hydrophobic peptides in aqueous solution in the hydrophilic pore (lower panel). The pore walls are indicated by horizontal black lines. The color-scale on the right-hand side indicates changes of the peptide density. 8114 DOI: 10.1021/la9006058
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Figure 4. Density profiles of peptides in aqueous solution in the pores: hydrophilic peptides in hydrophobic (red line) and hydrophilic (black line) pores (left vertical axis); hydrophobic peptides in the hydrophilic pore (blue line, right vertical axis). The scales of the left and right are proportional to the molecular weights of the hydrophilic and hydrophobic peptides.
their longest axes are highly isotropic (left panel in Figure 6) and only a slight preferential orientation of these axes parallel to the wall can be noticed. The situation is quite different in the case of strong adsorption of the peptides at interfaces (right panel in Figure 6). The localization near the interfaces essentially enhances the orientational ordering of the peptides and makes their longest axes align parallel to the interfaces. The degree of peptide aggregation was characterized by the parameter R, which denotes the probability to find more than two-thirds of all peptides in the largest peptide cluster.3 The distance between the centers of mass of two peptides was used as a connectivity criterium: two peptides are considered to belong to one cluster if this distance does not exceed some critical value rc. The dependences of the aggregation parameter R on the distance rc are shown in Figure 7. The degree of aggregation of the hydrophobic and hydrophilic peptides in the bulk solutions is quite similar (see upper panel in Figure 7). It can be compared with the similar dependences obtained for the aqueous solutions of FLVHS peptides.3 The degree of aggregation is noticeably weaker in the latter case in a wide range of rc. This reflects a weaker propensity of these peptides to aggregation. On the other hand, the presence of the methyl caps in FLVHS peptides (which were absent in the peptides studied in the present paper) could shift the equilibrium interpeptide distances in the aggregate to higher values. The aggregation of the hydrophilic peptides becomes weaker in both hydrophilic and hydrophobic pores (see middle panel in Figure 7), as inferred from the shift of the dependence R(rc) to a higher rc values. The situation with the hydrophobic peptides is opposite (lower panel in Figure 7). The aggregation of the hydrophobic peptides is slightly fostered due to the confinement in the hydrophilic pores and it enhances drastically upon confinement in the hydrophobic pore. The shift of the dependence R(rc) to lower rc values may also indicate formation of closely packed aggregates characterized by β-sheets with interpeptide distances of about 0.5 nm. This is supported by the increasing average number of interpeptide H-bonds per one peptide (from 11.8 to 17.1) and by the decreasing number of intrapeptide H-bonds (from 7.6 to 4.6) upon peptide adsorption on the hydrophobic surface. Langmuir 2009, 25(14), 8111–8116
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Figure 5. Density profiles of hydrophobic peptides in the slab of aqueous solution (left panel, red line) and in aqueous solution in the hydrophobic pore (right panel, red line). The density profiles of the centers of mass of the peptides are shown by the blue lines. The midpoints of the liquid-vapor interface and the pore walls are shown by the black dashed and solid lines, respectively.
Figure 6. Probability distribution of the angle R between the pore wall or the liquid-vapor interface and the vector connecting two most distant peptide heavy atoms.
The change of the degree of peptide aggregation by the confinement also yields information about the character of the peptide aggregation. In Figure 8, the number nH of water-peptide H-bonds is shown as a function of the aggregation parameter R at rc = 0.9 nm (the case of the hydrophobic peptides inside the hydrophobic pore is excluded as nH is strongly affected by peptide adsorption). As can be seen from Figure 8, nH decreases upon aggregation of hydrophilic peptides. This indicates that aggregation of these peptides occurs predominantly via direct contacts between hydrophilic groups of the peptides (this may be called as the “hydrophilic aggregation”), which become less accessible for water molecules upon formation of the peptide aggregate, thus rendering its surface effectively more hydrophobic. Conversely, nH increases upon aggregation of the hydrophobic peptides. In this case, formation of the peptide aggregate occurs predominantly via formation of close contacts between hydrophobic patches of the peptides (“hydrophobic aggregation”). Accordingly, the surface of the peptides exposed to liquid water becomes effectively more hydrophilic upon peptide aggregation. Similar character of aggregation was also observed for the hydrophobic FLVHS peptides.3
Discussion The results presented show that even a single extrinsic factor such as the water-mediated interaction between peptides and Langmuir 2009, 25(14), 8111–8116
Figure 7. Dependence of the aggregation parameter R on the distance rc used as a criterion for interpeptide connectivity. Upper panel: bulk aqueous solutions of the peptides. Middle panel: aqueous solution of hydrophilic peptides in pores. Lower panel: aqueous solution of hydrophobic peptides in pores.
surfaces has a drastic influence on peptide aggregation phenomena. Importantly, this influence depends on the character of peptide aggregation and on the strength of the water-surface interaction. The effect of water-mediated peptide-surface interactions is strongly determined by the balance of direct peptidesurface and water-surface interactions. If hydrophilic residues DOI: 10.1021/la9006058
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Figure 8. Dependence of the number nH of water-peptide H-bonds on the aggregation parameter R for hydrophilic (left panel) and hydrophobic (right panel) peptides in liquid water.
dominate the peptide‘s primary structure, it is energetically more favorable that such peptides stay hydrated, i.e., remain surrounded by at least one water layer. This trend is enhanced by a hydrophilic character of the surface and is opposed by a hydrophobic surface. However, even in the latter case the tendency of the hydrophilic peptides to stay hydrated remains dominating and they are repelled from the surface (see Figure 4). Hence, hydrophilic peptides should usually be repelled from a surface as direct peptide-surface contacts are energetically unfavorable even in the case of strongly hydrophobic paraffin-like surfaces. In contrast, hydrophobic peptides prefer to be dehydrated and the direct contacts with a surface provide energetically more favorable
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states. However, this trend can be overcome if the surface is hydrophilic enough. Near hydrophilic silica-like surfaces, the tendency of the surface to be hydrated overcomes the tendency of the hydrophobic peptides to be dehydrated; consequently, the peptides are repelled from the surface. The data clearly show that confinement in pores can cause both enhancement and weakening of peptide aggregation. In particular, we may expect weaker aggregation of hydrophilic peptides and stronger aggregation of hydrophobic peptides in pores (see middle and low panels in Figure 7). The possibility to weaken peptide aggregation by confinement of the aqueous solution of hydrophilic peptides in pores may be useful in pharmaceutical applications. The most drastic surface effect on aggregation is observed when hydrophobic peptides adsorb on hydrophobic surfaces or at the liquid-vapor interface. In both the cases, the degree of peptide aggregation is strongly enhanced and the ordering effect of the surface causes alignment of the peptides parallel to the surface. Both factors should promote formation of intermolecular β-sheets, which is a key structural element of amyloid fibrils. Thus, for hydrophobic peptides, the formation of amyloid fibrils may be expected first of all near hydrophobic surfaces. This observation agrees with experimental studies on Aβ peptides, which exhibit formation of tightly packed peptide layers on hydrophobic surfaces.11,12,16 Acknowledgment. Financial support from the International Max-Planck Research School in Chemical Biology and from the :: Zentrum fur Angewandte Chemische Genomik is gratefully acknowledged.
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