What Determines the Thermal Stability of the Hydrogen-Bonded Water

Mar 15, 2011 - Physical Chemistry, Dortmund University, Otto-Hahn-Str. 6, Dortmund, D-44227, Germany. J. Phys. Chem. Lett. , 2011, 2 (7), pp 765–769...
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LETTER pubs.acs.org/JPCL

What Determines the Thermal Stability of the Hydrogen-Bonded Water Network Enveloping Peptides? Alla Oleinikova* and Ivan Brovchenko Physical Chemistry, Dortmund University, Otto-Hahn-Str. 6, Dortmund, D-44227, Germany ABSTRACT: Hydrogen-bonded network of hydration water breaks upon heating at the temperature Tt via a quasi-2D percolation transition. Near model structureless surfaces, Tt is found to be strongly sensitive to the average energy Uws of the interaction between surface and water molecules in the hydration shell. In contrast, Tt ≈ 307 K is found near various peptides, indicating that the percoltion transition of hydration water is practically not sensitive to the peptide structure and Uws. This temperature is close to the temperature interval where the biological activity of living organisms is maximal. Insensitivity of Tt to the peptide structure is evidence that the thermal stability of hydration water network is determined by the cooperative hydration of the peptide backbone, whose chemical structure is identical for all peptides. SECTION: Macromolecules, Soft Matter

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tructure and functioning of biomolecules depend strongly on the properties of hydration water. The conformational transitions of biomolecules and the qualitative changes of the properties of hydration water often accompany each other. Experimental studies of low-hydrated lysozyme powder indicate a rapid change of water dynamics at ∼345 K1 when lysozyme undergoes denaturation. In liquid water, the heat-induced denaturation of lysozyme is preceded by the breaking of the hydrogen(H)-bonded network at ∼320 K2 and by the collapse of the hydration shell.3 Simulation studies of water water hydrogen bonding within the hydration shells of peptides show that a spanning hydrogen-bonded network of hydration water homogeneously envelopes a peptide at low temperatures. This network breaks upon heating into an ensemble of small clusters, and this process can be well-described as a quasi-2D percolation transition.4 6 This transition occurs in the biologically relevant temperature range (between 300 and 330 K) and can affect the conformational properties of peptides in water.5 7 Higher thermal stability of the H-bonded water network was found in the hydration shells of thermophilic proteins.8 Thermal break of the H-bonded network causes rapid changes of some thermodynamic properties of hydration water. Its thermal expansion coefficient increases by ∼30%.9 The components of the specific heat Cp undergo redistribution upon destruction of the H-bonded water network: the contribution due to the interactions within hydration shells decreases, whereas the contribution due to the interaction between hydration and bulk water increases.10 This is in agreement with increasing activation of the exchange between bulk water and hydration water of a model protein seen at ∼300 K.11 Such changes of the properties of hydration water make the surface of a biomolecules effectively more hydrophobic, which can provoke conformational changes and aggregation of peptides in water. It is not clear how the percolation transition of hydration water depends on the chemical structure and conformation of a peptide r 2011 American Chemical Society

and why it occurs in such a narrow temperature interval for various peptides. To answer these questions, in this Letter, we clarify how the thermal stability of H-bonded network of hydration water depends on the overall hydrophobicity (hydrophilicity) of a surface. We characterize the percolation transition of hydration water by the spanning probability (SP), which is the probability that the largest H-bonded water cluster includes more than one half of all water molecules in the hydration shell. SP is the fraction of the analyzed configurations with the size of the largest water cluster exceeding Nw/2, where Nw is a number of water molecules in the hydration shell in the respective configuration. We analyze SP for six peptides studied so far by molecular dynamic simulations in liquid model SPCE water: elastin-like peptide (ELP),5,7 GNNQQNY,10 NFGAIL,10 Aβ42,9 hIAPP, and hIAPPS.12 AMBER94 force field was used for ELP, whereas OPLS force field was used for all other peptides studied. The temperature dependences of SP for six peptides are shown in Figure 1. All dependences SP(T) are sigmoid-like and close in the temperature range. The percolation transition in a finite system, such as a hydration shell of a peptide, is rounded, and SP changes from 1 (the largest cluster of hydration water always includes more than Nw/2 molecules) to 0 (the largest cluster of hydration water never includes more than Nw/2 molecules) upon heating in some finite temperature interval. The sizes of the peptides studied differ strongly. For example, the hydration shell of Aβ42 includes ∼400 molecules at low temperatures, whereas this number is ∼80 in the case of NFGAIL peptide. The linear size of a quasi-2D hydration shell can be measured approximately by the length L = SASA0.5, where SASA is the solvent accessible surface area of a peptide. Received: February 8, 2011 Accepted: March 10, 2011 Published: March 15, 2011 765

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for the difference in the dependences SP(T). To test this assumption, we have performed the finite-size scaling analysis of SP(T). The temperature corresponding to an arbitrarily chosen value of SP was estimated from the fits of SP(T) to sigmoid function. The temperatures, corresponding to three values of SP, are shown in the upper panel of Figure 2 as a function of L 1. In the macroscopic limit, the temperature dependence of the spanning propability SP(T) turns to a step-like function, which assumes that the dependences such as those shown in the upper panel of Figure 2 merge together, when L 1 f 0. The linear fits of the dependences in the upper panel of Figure 2 show the percolation transition in the limit L 1 f 0 at Tt between 300 and 310 K. The critical value of SP at the percolation threshold depends on the definition of the spanning probability (numerous definitions are possible) but only weakly depends on the system size.13,14 Thus, the temperature corresponding to the critical value of SP should exhibit the weakest dependence on L 1. We have found that for the spanning probability used in our studies, the temperature corresponding to SP ≈ 0.73 is roughly independent of the system size. This yields the temperature of the percolation transition Tt = (307 ( 5) K (horizontal line in the upper panel of Figure 2). Using the value Tt obtained above, the temperature dependences of the spanning probability for various peptides can be put on a scaling plot. (See the lower panel in Figure 2.) The collapse of the data for various peptides indicates that the percolation transition of hydration water is highly universal and supports the assumption that the size of the hydration shell is the main factor responsible for the difference of the dependences SP(T) shown in Figure 1. This finding is surprising because Tt is found to be practically not sensitive to the chemical structure and conformation of peptides. The degree of hydrophobicity of the considered set of peptides varies in a wide range and can be characterized by the average energy of water peptide interaction Uws in the hydration shell. Uws ≈ 1.7 kcal/mol for strongly hydrophobic NFGAIL peptide, whereas Uws ≈ 2.4 kcal/mol for strongly hydrophilic GNNQQNY peptide.10 The hydrophobicities of the other four peptides studied are in between these two almost limiting cases. One can expect two opposite effects of water peptide interactions on the H-bonded network of hydration water. An overall strengthening of the water surface interaction makes the hydration water more dense, which promotes connectivity of water water H-bonds and should cause the shift of Tt to higher temperatures. The direct water-surface H-bonds can damage the water water connectivity in the hydration shell, which should cause the shift of Tt to lower temperatures. To separate these two effects on Tt, we have studied water near model structureless (smooth) surfaces with the water surface interaction depending on the distance to the surface only. The well depth U0 of the (9,3) Lennard-Jones water-surface potential was chosen to be 0.39, 1.93, 3.08, and 4.62 kcal/mol to mimic the surfaces from strongly hydrophobic (paraffin-like) to strongly hydrophilic (metallic-like). Constant-volume Monte Carlo (MC) simulations of TIP4P liquid water were performed in cylindrical pores of a radius 25 Å and length 50 Å along their liquid vapor pore coexistence curves15 with a temperature step 10 K. At the lowest temperature studied (T = 270 K), the simulated system was composed of ∼2800 to ∼3000 water molecules in the strongly hydrophobic and in the strongly hydrophilic pore, respectively. Water properties were analyzed each 1000th MC step and averaged over ∼5  104 configurations. The

Figure 1. Temperature dependence of the spanning probability SP near structureless surfaces (open symbols) and near peptides (solid symbols with lines): Aβ42,9 ELP,5,7 GNNQQNY and NFGAIL,10 hIAPP and hIAPPS.12

Figure 2. Upper panel: The temperatures corresponding to SP = 0.50, 0.73, and 0.90 as a function of the reverse system size L 1 for water in the hydration shell of several peptides (symbols). The linear fits are shown by lines. Lower panel: Scaling plot of the spanning probability SP for the peptides shown in Figure 1 with Tt = 307 K (symbols) and for the structureless surface with U0 = 1.93 kcal/mol and Tt = 321 K (line).

Such approach yields L ≈ 2.96, 3.25, 4.10, 5.50, 5.53, and 6.20 nm for NFGAIL, GNNQQNY, ELP, hIAPP, hIAPPS, and Aβ42, respectively. A visual inspection and the fit of the dependences SP(T) shown in Figure 1 to the sigmoid function evidence that the width of a sigmoid decreases with increasing L. We can assume that the different size of peptides is the main factor responsible 766

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Figure 3. Dependence of the temperature of the percolation transition Tt on the average energy of water surface interaction Uws (left panel) and on the density of hydration water Fh (right panel) calculated at T = Tt.

first minimum in the liquid density profile of water F(r)16 was used to define the width of a hydration shell. Near the surfaces with U0 = 1.93, 3.08, and 4.62 kcal/mol, a minimum of F(r) is located at r ≈ 4.5 Å and changes negligibly upon heating.16 The hydration shell is notably wider near strongly hydrophobic surface, where the first minimum of F(r) is estimated at r ≈ 5.3 Å.6 The connectivity of water molecules within the hydration shell was characterized using analysis of water clustering similar to the previous studies.4,5 Two water molecules were considered to be H-bonded when the distance between their oxygens did not exceed 3.5 Å and their interaction energy was below 2.6 kcal/mol. The temperature dependences of SP for hydration water near various structureless surfaces shown in Figure 1 (open symbols) indicate that the temperature-induced percolation transition shifts strongly to higher temperatures upon strengthening the water surface interaction. The temperature Tt, which corresponds to SP = 0.73, shifts from 295 K for hydrophobic surface with U0 = 0.39 kcal/mol to 395 K for hydrophilic surface with U0 = 4.62 kcal/mol. The scaling plot for the spanning probability in the case of a structureless surface with U0 = 1.93 kcal/mol agrees well with that for peptides. (See the lower panel in Figure 2.) To compare the water surface interaction near structureless and biological surfaces, we have calculated the average energy of water surface interaction, Uws, for the hydration water near all studied sturctureless surfaces. Uws always exceeds U0 and only slightly increases upon heating. Below, we use the value of Uws at T = Tt in the analysis. The values of Uws for peptides have been estimated by linear interpolation between the calculated values of Uws for GNNQQNY and NFGAIL peptides, assuming the linear relation between Uws and the average hydrophobicity of amino acids17 of the peptide. The temperature dependences of Tt on the energy of water surface interaction Uws (left panel in Figure 3) are very different for water near model structureless surfaces and near peptides. For model surfaces, this dependence is close to linear: Tt increases by ∼25 K upon strengthening the water surface interaction by 1 kcal/mol. For peptide surfaces, Tt is almost independent of Uws. Quite similar discrepancy between structureless and peptide surfaces is also seen in the dependences of Tt on the density of hydration water Fh (right panel in Figure 3). So, Tt of water near peptides is almost independent of Uws and on Fh. Moreover, slight decrease in Tt with the strengthening

Figure 4. Spanning probabilities as a function of an average number nww of hydrogen bonds that a water molecule forms with neighbors in the hydration shell.

water surface interaction and increasing Fh can be noticed. This behavior can be attributed to the effect of the direct H-bonds between water and peptides, which are absent in the case of structureless surfaces. The average number of the water peptide H-bonds per water molecule in the hydration shell, nws, is ∼0.22 and ∼0.37 H bonds for strongly hydrophobic peptide NFGAIL and strongly hydrophilic peptide GNNQQNY, respectively. H-bonds between water molecules and peptide can worsen their ability to form water water H-bonds within the hydration shell, which should cause a decrease in Tt with increasing peptide hydrophilicity. This is supported by the observed weakening of the H-bonded water network at the surface of the hIAPP peptide upon increasing the number of water peptide H-bonds and increasing the density of hydration water. However, this effect is small: the increase in nws by 0.1 causes the decrease in Tt by just a few degrees. This can explain a slight decrease in Tt upon increasing peptide hydrophilicity but not the strong difference in the temperature dependences Tt(Uws) and Tt(Fh) for structureless surfaces and peptides shown in Figure 3. To compare further the percolation transitions of water near structureless surfaces and near peptides, we have analyzed the average number of water water H-bonds, nww, that a water molecule forms within the hydration shell. The dependences of the spanning probability on nww for structureless surfaces and for peptides are shown in the upper panel of Figure 4. There is a systematic shift of the dependence SP(nww) with increasing system size. To eliminate the size effect, we plot the dependence of nww at the percolation threshold (SP = 0.73) on the reverse system size L 1 in the lower panel of Figure 4. The dependence for peptides gives ntww ≈ 2.0 at the percolation threshold in macroscopic limit, whereas the data points for structureless surfaces deviate strongly from this dependence. The value of ntww depends on the percolation problem considered.18 The temperature-induced percolation transition of 767

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The Journal of Physical Chemistry Letters hydration water in fully hydrated systems is a site-bond percolation problem because both the density of water in the hydration shell and the probability of water water H-bonds change with temperature. It is closer to the bond-percolation problem because the density of hydration water is far from the threshold of the site percolation. For the random bond percolation on 2D lattices, the average number of bonds at the percolation threshold is ∼2.0 and only slightly depends on the lattice structure.18 Therefore, we expect that the value of ntww only weakly depends on the surface properties. Some changes of ntww are expected because of the different structure (density) of hydration water near hydrophobic and hydrophilic surfaces. As can be seen from Figure 4, these changes are rather small for structureless surfaces despite the strong change of the density of hydration water (Figure 3). Obviously, the strong difference of the values ntww for water near structureless surfaces and near peptides can not be explained by the different structure of hydration water. The insensitivity of Tt for water near peptides to their chemical structure can be understood if the thermal break of the H-bonded network of hydration water around peptides is determined by the identical part of these polymers, that is, by the peptide backbone formed by the repeating unit N C CdO. Because of the polymer structure of peptides, the spanning network of hydration water is more sensitive to the water water H-bonds near such units than to those near amino acids. There is a close similarity in the hydration of a peptide backbone and of a poly(N-isopropylacrilamide) (PNIPAM).19 PNIPAM in water undergoes conformational changes and aggregation upon heating at ∼310 K, and this temperature practically does not depend on the polymer size and concentration in contrast with other polymers, such as poly(ethylene oxide)20 and poly(2-isopropyl-2-oxazioline).21 This behavior was attributed to the “cooperative hydration” of PNIPAM, which is to the sequential H-bonds between water molecules, which are also H-bonded with polymer.22,23 Upon heating, hydration water undergoes qualitative changes at ∼310 K,24 and the sequential water water H bonds along the PNIPAM chain break,25 which can be considered as a thermal break of hydration water network. The hydrophilic part of the repeating units of both peptides and of PNIPAM is the same (HN CdO), which can explain why the water network breaks almost at the same temperature in both cases. Our studies show that hydration water at extended peptide surfaces undergoes qualitative changes within narrow temperature interval around 307 K. This is surprisingly close to the temperatures of the maximal activity of living organisms.26 In particular, organisms able to control their body temperature (mammals and birds) keep it between 309 and 317 K. At the temperature of the percolation transition, the information entropy of H-bonded water clusters in terms of the diversity of their sizes diverges,27 which can play some role in intrinsically nonequilibrium biological processes. This poses an intriguing question about the value of Tt for another important class of biopolymers, polynucleotides.

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’ REFERENCES (1) Zhang, Y.; Lagi, M.; Liu, D.; Mallamace, F.; Fratini, E.; Baglioni, P.; Mamontov, E.; Hagen, M.; Chen, S.-H. Observation of High-Temperature Dynamic Crossover in Protein HydrationWater and its Relation to Reversible Denaturation of Lysozyme. J. Chem. Phys. 2009, 130, 135101. (2) Hedoux, A.; Ionov, R.; Willart, J.-F.; Lerbret, A.; Affouard, F.; Guinet, Y.; Descamps, M.; Prevost, D.; Paccou, L.; Danede, F. Evidence of a Two-Stage Thermal Denaturation Process in Lysozyme: A Raman Scattering and Differential Scanning Calorimetry Investigation. J. Chem. Phys. 2006, 124, 014703. (3) Koizumi, M.; Hirai, H.; Onai, T.; Inoue, K.; Hirai, M. Collapse of the Hydration Shell of a Protein prior to Thermal Unfolding. J. Appl. Crystallogr. 2007, 40, 175–178. (4) Oleinikova, A.; Brovchenko, I.; Smolin, N.; Krukau, A.; Geiger, A.; Winter, R. Percolation Transition of Hydration Water: From Planar Hydrophilic Surfaces to Proteins. Phys. Rev. Lett. 2005, 95, 247802. (5) Brovchenko, I.; Krukau, A.; Smolin, N.; Oleinikova, A.; Geiger, A.; Winter, R. Thermal Breaking of Spanning Water Networks in the Hydration Shell of Proteins. J. Chem. Phys. 2005, 123, 224905. (6) Brovchenko, I.; Oleinikova, A. Interfacial and Confined Water; Elsevier, Amsterdam, 2008. (7) Krukau, A.; Brovchenko, I.; Geiger, A. Temperature-Induced Conformational Transition of a Model Elastin-Like Peptide GVG(VPGVG)3 in Water. Biomacromolecules 2007, 8, 2196–2202. (8) Sterpone, F.; Bertonati, C.; Briganti, G.; Melchionna, S. Key Role of Proximal Water in Regulating Thermostable Proteins. J. Phys. Chem. B 2009, 113, 131–137. (9) Brovchenko, I.; Burri, R. R.; Krukau, A.; Oleinikova, A.; Winter, R. Intrinsic Thermal Expansivity and Hydrational Properties of Amyloid Peptide Aβ42 in Liquid Water. J. Chem. Phys. 2008, 129, 195101. (10) Oleinikova, A.; Brovchenko, I.; Singh, G. The Temperature Dependence of the Heat Capacity of Hydration Water near Biosurfaces from Molecular Simulations. Europhys. Lett. 2010, 90, 36001. (11) Melchionna, S.; Briganti, G.; Londei, P.; Cammarano, P. Water Induced Effects on the Thermal Response of a Protein. Phys. Rev. Lett. 2004, 92, 158101. (12) Brovchenko, I.; Andrews, M. N.; Oleinikova, A. Volumetric Properties of Human Islet Amyloid Polypeptide in Liquid Water. Phys. Chem. Chem. Phys. 2010, 12, 4233–4238. (13) Hovi, J.-P.; Aharony, A. Scaling and Universality in the Spanning Probability for Percolation. Phys. Rev. E 1996, 53, 235–253. (14) Skvor, J.; Nezbeda, Y.; Brovchenko, I.; Oleinikova, A. Percolation Transition in Fluids: Scaling Behavior of the Spanning Probability Functions. Phys. Rev. Lett. 2007, 99, 127801. (15) Brovchenko, I.; Oleinikova, A. Water in Nanopores III: Surface Phase Transitions of Water on Hydrophilic Surfaces. J. Phys. Chem. C 2007, 111, 15716–15725. (16) Oleinikova, A.; Brovchenko, I.; Winter, R. Volumetric Properties of HydrationWater. J. Phys. Chem. C 2009, 113, 11110–11118. (17) Kyte, J.; Doolittle, R. F. A Simple Method for Displaying the Hydropathic Character of a Protein. J. Mol. Biol. 1982, 157, 105–132. (18) Stauffer, D.; Aharony, A. Introduction to Percolation Theory; Taylor and Francis: London, 1992. (19) Meersman, F.; Wang, J.; Wu, Y.; Heremans, K. Pressure Effect on the Hydration Properties of Poly(N-isopropylacrylamide) in Aqueous Solution Studied by FTIR Spectroscopy. Macromolecules 2005, 38, 8923–8928. (20) Bae, Y. C.; Lambert, S. M.; Soane, D. S.; Prausnitz, J. M. CloudPoint Curves of Polymer Solutions from Thermooptical Measurements. Macromolecules 1991, 24, 4403–4407. (21) Diab, C.; Akiyama, Y.; Kataoka, K.; Winnik, F. M. Microcalorimetric Study of the Temperature-Induced Phase Separation in Aqueous Solutions of Poly(2-isopropyl-2-oxazolines). Macromolecules 2004, 37, 2556–2562. (22) Okada, Y.; Tanaka, F. Cooperative Hydration, Chain Collapse, and Flat LCST Behavior in Aqueous Poly(N-isopropylacrylamide) Solutions. Macromolecules 2005, 38, 4465–4471.

’ AUTHOR INFORMATION Corresponding Author

*E-mail: [email protected].

’ ACKNOWLEDGMENT We gratefully acknowledge financial support form DFG (grant OL314/1). 768

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(23) Tanaka, F.; T. Koga, T.; Winnik, F. Temperature-Responsive Polymers in Mixed Solvents: Competitive Hydrogen Bonds Cause Cononsolvency. Phys. Rev. Lett. 2008, 101, 028302. (24) Sekine, Y.; Ikeda-Fukazawa, T. Temperature Dependence of the Structure of Bound Water in Dried Glassy Poly-N,N,-dimethylacrylamide. J. Phys. Chem. B 2010, 114, 3419–3425. (25) Ono, Y.; Shikata, T. Contrary Hydration Behavior of N-Isopropylacrylamide to its Polymer, P(NIPAm), with a Lower Critical Solution Temperature. J. Phys. Chem. B 2007, 111, 1511–1513. (26) Brovchenko, I.; Oleinikova, A. Which Properties of a Spanning Network of HydrationWater Enable Biological Functions?. ChemPhysChem 2008, 9, 2695–2702. (27) Tsang, I. R.; Tsang, I. J. Cluster Size Diversity, Percolation, and Complex Systems. Phys. Rev. E 1999, 60, 2684–2698.

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