Specific Interactions of Neutral Side Chains of an Adsorbed Protein

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Specific Interactions of Neutral Side Chains of an Adsorbed Protein with the Surface of #-Quartz and Silica Gel Alexey V. Odinokov, and Alexander A. Bagaturyants J. Phys. Chem. B, Just Accepted Manuscript • DOI: 10.1021/acs.jpcb.5b04064 • Publication Date (Web): 18 Jun 2015 Downloaded from http://pubs.acs.org on June 19, 2015

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The Journal of Physical Chemistry

Specific Interactions of Neutral Side Chains of an Adsorbed Protein with the Surface of α-Quartz and Silica Gel Alexey V. Odinokova*, Alexander A. Bagaturyantsa,b a

Photochemistry Center, Russian Academy of Sciences, Novatorov street 7a, building 1, Moscow 119421, Russia b

Moscow Engineering Physics Institute, Kashirskoe hwy 31, Moscow 115409, Russia

*Corresponding author Email: [email protected] Tel: 7 495 935 01 15 Fax: 7 495 936 77 53

ACS Paragon Plus Environment

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ABSTRACT

Many key features of the protein adsorption on the silica surfaces still remain unraveled. One of the open questions is the interaction of non-polar side chains with siloxane cavities. Here, we use non-equilibrium molecular dynamics simulations for the detailed investigation of the binding of several hydrophobic and amphiphilic protein side chains with silica surface. These interactions were found to be a possible driving force for protein adsorption. The free energy gain was larger for the disordered surface of amorphous silica gel as compared to α-quartz, but the impact depended on the type of amino acid. The dependence was analyzed from the structural point of view. For every amino acid an enthalpy-entropy compensation behavior was observed. These results confirm a hypothesis of an essential role of hydrophobic interactions in protein unfolding and irreversible adsorption on the silica surface.


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INTRODUCTION Adsorption of biological macromolecules on inorganic substrates is of great interest for the applications in biotechnology1. An impact of adsorption on the structure and activity of proteins governs the toxicity of nanoparticles and other artificial objects immersed into the organism, which is of fundamental importance for medicine2. One of the most popular substrates forming bioactive surfaces is silicon dioxide (SiO2) in the form of α-quartz or silica gel. It is widely known that, upon adsorption on the SiO2, peptides often undergo severe conformational changes, unfold and lose their activity3. The detailed picture of these phenomena is based on the type of the surface, its chemical modification, peptide sequence, pH of the medium and buffer salt concentration4,5. Usually, the driving force of protein adsorption on silica is attributed mainly to the interactions of positively charged side chains with negatively charged surface oxygens. These strong and long-range forces ensure binding of dissolved protein molecules to the surface. Subsequent conformational changes of the polypeptide chain are, on the other hand, governed by various types of interactions, among which hydrophobic effects also matter6. Apolar side chains can interact with siloxane sites by expelling water molecules. This effect, called hydrophobic dehydration, is expected to facilitate protein unfolding and irreversible adsorption7,8. It has been shown that some hydrophobic side chains, especially proline, can bind to α-quartz via burial in the surface interstices9. Moreover, hydrophobic interactions can directly influence total adsorption equilibria, if surface charge of the silica is cancelled by acidic environment10.


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It should be noted that experimental estimation of the impact of a single non-polar side chain on the protein adsorption remains a challenging task. The first reason is that amino acids in aqueous solution exist in zwitterionic form, so their interaction with SiO2 surface is governed by the coulombic attraction of N-terminus and not by the hydrophobic interactions. On the other hand, any experiment concerning polypeptide adsorption produces averaged information, which is difficult to split into the contributions of individual residues. Conclusions are usually derived from the comparative analysis of experimental data on the adsorption of different polypeptide sequences on different surfaces7,8. This makes atomistic simulations a promising way to obtain missing details. In light of this, we set a goal of describing the process of protein adsorption on the non-modified SiO2 surface with the aid of molecular dynamics (MD) simulations. By applying the computer modeling, we obtained detailed data about structural features and thermodynamic properties of the neutral side chains bonded to the SiO2. COMPUTATIONAL METHODOLOGY Definition of the computed quantities In our work we did not seek for complete computation of the protein adsorption energy and full sampling of the conformational changes. Although such a problem can be solved, the majority of successful works in this area concerns smother surfaces, e.g. graphite11 or selfassembled monolayers12. We are not sure about the real possibility of performing this kind of work for the silica gel. Instead of this, we created a set of sample protein configurations by sequential heating and cooling (a typical example is shown in Fig 1) and focused on estimating a binding affinity of individual side chains. To measure binding affinity we used free energy difference ∆∆G = ∆G loc − ∆G ref ,

(1)


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where the quantity ∆GX corresponds to the free energy difference of the annihilation process, in which all intermolecular interactions of the side chain atoms are switched to zero and Cβ atom becomes hydrogen. In the result, the given amino acid (state A) “mutates” to glycine (state B). Index loc denotes the calculation for actual local environment (including water, SiO2 and remaining protein residues). Index ref specifies the reference calculation for the model tripeptide GLY-AA-GLY in water, which is aimed to model amino acid AA in the ideal water environment. For the estimation of the enthalpy difference we calculated average potential energy of the system in the initial and final states: ∆∆H = U

where

L

X A

loc B

− U

loc A

+ U

ref

− U

B

ref A

,

(2)

denotes averaging over MD trajectory with normal amino acid, and

L

X B

corresponds to glycine. To compute free energy differences from the right side of Eq (1) we first used Crooks Gaussian Intersection method (CGI13). This method implied the use of forward and reverse paths for annihilation process. If a sufficiently large number of MD runs are performed, then free energy difference is expressed as14  W f − Wr ± ∆G = 1 1  σ 12 σ 22 −  2 2  1

σ1

σ2

(W

f

− Wr )

σ 12σ 22

2

 1 1  σ + 2  2 − 2  ln 2  σ1 σ 2  σ1

 ,  

(3)

where W f , σ f , Wr and σ r are the means and standard deviations of the non-equilibrium work for the forward and reverse paths, respectively. Using this protocol, we obtained the value of 12.5 + 0.9 kJ mol-1 for tryptophan tripeptide, which is quite close to the -15.0 + 1.0 kJ mol-1, found in Ref. 14 with the same computational setup, but using OPLS-aa force field15.


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Although CGI method allows for reliable computation of the free energy of side chain annihilation14, its application to complex systems, such as folded or adsorbed polypeptide, becomes impractical. The problem arises from the multitude of trapped conformations in nearly annihilated state of the side chain. It was found to be almost impossible to conduct a reverse process with the side chain atoms appearing in the system because of the interference of the surface and other protein residues. Therefore, we decided on straightforward application of Jarzynski equation16. In this case only forward process is simulated and the free energy is obtained via exponential averaging:

 W  ∆G = − k BT ln exp  − f   k BT 

,

(4)

A

where T is the temperature and kB is the Boltzmann constant. In order to confirm the suitability of the current computational setup, we produced a set of test runs following Eqs (3) and (4) for the same model tripeptides with the same number and duration of trajectories. The obtained values deviated from the results of CGI method within the standard error.


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Figure 1. Overall view of the simulation box with silica gel slab and adsorbed protein chain. Water molecules are not shown for clarity.

Details of the molecular dynamics simulations All molecular dynamics simulations were performed using GROMACS-5.0.2 package17. The CHARMM2718 force field for proteins was combined with additional parameters for SiO219 and TIP3P20 water model. Starting conformation of HAP was borrowed from the experimental structure of HAP/α-BTX complex21 and then relaxed in water during 50 ns. While atomic coordinates and molecular topology for α-quartz was reported in Ref 19, the model construction for silica gel required special attention. We started from the equilibrium box of α-quartz and run MD simulation at 7000 K using reactive potentials22. Then we slowly annealed the system to 300


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K and obtained amorphous silica gel. The same algorithm was used to simulate MCM-41 mesoporous silica as reported in Ref. 23, where it was described in details. For this model mean value of the O-Si-O angle equals to 108.5o, which is in reasonable agreement with experimental data (109.3o for SiO2 glass24). Numerical estimates of the mean value and full width half maximum (FWHM) for the Si-O-Si angle are 137o and 18o, respectively. These values can be successfully related to some experimental counterparts, for example 143o±20o, as reported in Ref. 25. To obtain final structure of the silica slab, we cut the bulk silica cell in xy plane and added hydroxyl groups to all broken bonds. After that we randomly removed closely spaced silanol groups to form siloxane bridges until the surface density of silanols reached the value of 3.6 nm-2, which is less than in fully hydroxylated silica gels26 (5 nm-2) and close to the typical mesoporous silica27 (4 nm-2). The simulation box had the size of 3.4 and 3.1 nm in x and y direction, respectively, and included 34 terminal and 4 geminal silanol groups on the top surface of the silica slab. For the calculation of every ∆GX value a set of 30 MD trajectories was produced. Each trajectory lasted for 160 ps and consisted of two steps of equal length. At the first step atomic charges were linearly scaled to their final value, which was zero for all atoms that had to be annihilated. During the second step linear scaling was applied to the Lennard-Jones parameters. Contact surface areas were calculated using PyMOL Molecular Graphics System, Version 1.4.1, Schrödinger, LLC. The contact surface was defined as a piece of the solvent excluded surface (SES) of the side chain, which overlaps with the SES of neighboring moieties. The radius of the sample solvent was 0.14 nm.


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Figure 2. Amino acids with neutral side chains investigated in the present work. Dotted line highlights side chain fragments regarded as hydrophobic.

RESULTS AND DISCUSSION Description of the model system A hydroxylated cross-cut of α-quartz through the (011) plane and a surface of amorphous silica gel were chosen as the sample substrates. These two types of surfaces expose different patterns of siloxane cavities. The former has an arranged lattice of cavities of equal (and relatively small) size. The latter provides richer ensemble of hydrophobic binding sites of varying sizes and shapes, so the probability of specific binding is higher. For the sample adsorbate we took oligopeptide WRYYESSLLPYPD. This synthetic peptide is known as HAP (High Affinity Peptide28). It was developed as a specific ligand for α-bungarotoxin (α-BTX). Adsorption of HAP on the silica gel surface is of some importance from the perspective of developing a sensor chip sensitive to α-BTX. We chose it primarily for being a good test polypeptide. Its sequence includes positively charged arginine residue, which must be favorable


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for adsorption. The protein consists of 13 amino acids, with 10 of them having hydrophobic or amphiphilic side chains. To put it more exactly, there are 3 tyrosines, 2 leucines, 2 prolines, 2 serines and 1 tryptophane residue (see Fig 2). The existence of duplicates for the given amino acid allows to investigate the influence of its location in the polypeptide sequence and to discover an effect of neighboring residues.

Free energy of adsorption Free energies of “mutation” of every amino acid to glycine were calculated. The HAP sequence included 10 neutral aminoacids and 8 independent configurations were considered for every type of environment: protein loop in water, α-quartz and silica gel. The results for all 240 calculations are presented in Fig. 3. It is seen that for every type of environment side chain interactions (with rare exceptions) stabilize the current configuration as compared to the pure water. The main discrepancy between different environments consists in the distribution width and minimal possible values of ∆∆G. HAP in water exists in a form of beta-sheet structure stabilized with hydrophobic interactions of the side chains. Although visual inspection gives evidence of essential rearrangements of hydrophobic groups, free energy of “mutation” seems to vary in the limited interval.


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Figure 3. Free energy differences for every neutral side chain in the HAP sequence. Three cases were considered: native loop in water (red markers, left column for every amino acid), adsorption on the surface of α-quartz (blue markers, middle column) and silica gel (green markers, right column). Empty circles were used if no contact was found between the side chain and the surface. Conversely, ∆∆G for the case of SiO2 surface displays broad distribution due to the multitude of possible positions and orientations of the given side chain relative to the surface atoms and the other amino acids. Furthermore, the real experiment deals with macroscopic times, so the adsorbed state of the protein can be considered as almost fully equilibrated. In this case the majority of amino acids are supposed to occupy very advantageous binding sites, so the actual value of ∆∆G is close to the lowest point shown in Fig 3 (or even lower). It means that specific interactions of the side chains with the surface make adsorbed state energetically favored against dissolved beta-sheet structure. The effect for silica gel is more prominent than for α-quartz. In the case of silica gel some amino acids, namely proline and leucine show much broader distribution of ∆∆G with minimal values located well below their α-quartz counterparts. This observation illustrates an impact of larger cavities of silica gel on the protein adsorption. The most favorable cases of siloxane cavities occupied with the side chains are shown in Fig 4. From this figure the distinction between α-quartz and silica gel for leucine and proline becomes clear. The same effect can also be attributed to tyrosine. The most energetically favored conformations occur when tyrosine ring is located parallel to the large siloxane spot (see Fig 4), which can be encountered only in amorphous silica gel. But this did not happen even once for tyrosine residue in the third position, so in that case the advantage of silica gel was not visible in Fig 3.


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Figure 4. The most favorable siloxane cavities occupied with side chains. The results for αquartz are shown at the top row, while the bottom row corresponds to silica gel. Only the limited cluster of the closest SiO2 atoms is displayed. There is not a sufficiently large siloxane spot to contain tryptophan ring parallel to the surface in our model silica gel slab, so the distribution of ∆∆G in Fig 3 is almost the same for both substrates. But in reality, one can assume that some fraction of large enough siloxane cavities exists and the notable effect of the surface type on tryptophan binding is also expected. The only exception from the observed trend is serine. This comes as no surprise due to the small size of the side chain and its hydrophobic part. It has been shown that the presence of the motifs rich of leucine, proline and tryptophan residues in the peptide sequence enhances binding to α-quartz29,9. An influence of the specific binding of proline to the hydrophobic cavities in α-quartz on this process was also indicated9. The present work provides a basis for the extension of this conclusion to other hydrophobic and


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amphiphilic amino acids. The effect proved for α-quartz is obviously surface-dependent and the obtained data suggest that specific binding of side chains to silica gel can be even tighter.

Comparison to the experimental data for amino acids. Although we do not aware of any experimental studies concerning direct measurements of the adsorption of neutral side chains, the data for water solution of amino acids are available in the literature30. One can assume a hypothesis that the difference in free energy of adsorption between amino acids is mainly governed by the chemical nature of their side chains. It would be advantageous to find a correlation between experiment and numerical simulation, even bearing in mind all distinctions. Figure 5 contains a comparison between our results and the data from Ref. 30. The points seem to be scattered randomly. Apart from the possible inaccuracies in the model definition and simulation setup, this fact also has a physically relevant explanation. The absence of a correlation implies that the impact of the side chain on the adsorption of the individual amino acid molecule is not straightforward. We speculate that this is due to the decisive influence of the interaction between amino group and the charged silanol oxygen on the position and conformation of an adsorbed amino acid. Side chains in polypeptide sequence and in the amino acid molecules behave differently.


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Figure 5. Comparison between the calculated results and experimentally obtained adsorption free energies of amino acids on the silica gel.

Analysis of the contact areas To describe the constitution of local environment for any given configuration with simple geometrical criterion, we used a contact area (CA) of the given side chain with neighboring atoms. The most straightforward approach supposed that contact surface was formed by all atoms in the side chain and all atoms in any other residue except water molecules. For the betasheet structure in water no dependency was observed between ∆∆G and CA. We also used the second approach, which concerned only the contacts between the atoms of hydrophobic parts of the side chain and the medium. The results are shown in Fig 6. The correlation between ∆∆G and CA is slightly higher for the first approach (top row), but this dependence is still very noisy. The complications in finding a relationship between CA and free energies can be attributed to the impossibility of treating intermolecular interactions in terms of overlapping smooth surfaces at the length scale of individual atoms. The correlation is much more visible for silica gel as compared to α-quartz. Silica gel provides larger siloxane cavities, so larger CAs can be found in the system and the dependence becomes visible.


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Figure 6. Free energy differences versus contact area. The data is shown for α-quartz (left column) and silica gel (right column). Contact surface was formed by all atoms (top row) and only hydrophobic moieties (bottom row). A linear slope is given with dotted line, the correlation coefficients R are also presented.

Enthalpy-entropy compensation Additionally to the free energies of adsorption we calculated average potential energy of the total system before and after the annihilation process. When associated with the corresponding value for model tripeptide, this quantity represents enthalpy change upon binding. This made it possible to decompose free energy differences into enthalpic and entropic contributions. The result is presented in Fig. 7. For every type of amino acid different instances of side chain adsorption show clear enthalpy-entropy compensation (EEC) behavior, though with visible fluctuations. It is worthy of note that data points for pure water, α-quartz and silica gel are arranged along the same line, even if the regions they are scattered in do not coincide. This fact indicates an analogous mechanism of binding in these three cases. A phenomenon of enthalpy-


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entropy compensation is widespread in water solutions of proteins. It is often attributed to the induced changes in the water solvation shell31,32, which in its turn relates to the hydrophobic interactions33. The importance of the water structure near inorganic surface for the adsorption of hydrophobic side chains was emphasized earlier by Schneider et al. on the basis of molecular dynamics simulations34. The constant ratio of ∆∆H to T∆∆S for all three types of environment suggests that interactions of the protein side chains with hydrophobic spots on the surface have the same origins at the atomic level as in the case of protein folding or protein/ligand binding.

Figure 7. Enthalpy-entropy compensation plots for every amino acid type. Many systems possessing EEC also manifest isoequilibrium behavior. In the case of ideal compensation this is a strict law, but even moderate deviations can entirely disorganize temperature dependence of the free energy difference35. There are a number of experimental studies involving proteins that report a pronounced EEC36. The isoequilibrium effect was also proved to exist, e.g. for conformational changes of amino acids in unfolded oligopeptides37.


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Despite this, we were not been able to find any sign of isoequilibrium temperature for the data points presented in Fig. 7. The most probable cause is severe fluctuations of the calculated energy values.

CONCLUSIONS The computed free energy differences support a hypothesis that the protein adsorption on the unmodified SiO2 surface can be efficiently mediated by the interactions of non-polar side chains with siloxane spots. In accordance with experimental observations9,10, proline side chain can serve as an “anchor” that binds to the surface interstices. The similar effect can be postulated for tyrosine, leucine and tryptophan, but not for serine. We describe these interactions as side chain specific, since the free energies of adsorption depend on the type of amino acid and much less on the position in the polypeptide chain. The disordered structure of silica gel provides much richer ensemble of surface binding sites. Individual side chains occupy the most energetically favored sites, so the degree of chain unfolding and irreversible adsorption for silica gel is supposed to be higher than for α-quartz. Although we used one sample slab of silica gel as a model of SiO2 surface, the silica gel is known to be produced in a variety of forms with each of them possessing its own surface features. Any particular case has a different binding affinity with amino acids. Nevertheless, we expect that the obtained results concern the difference in basic properties of ordered (α-quartz) and disordered (silica gel) structures of SiO2, and therefore are valid for a wide range of systems at the qualitative level.

ACKNOWLEDGMENT


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This work was supported by the Russian Foundation for Basic Research (grant 13-03-12423). Calculations were performed using the facilities of the Joint Supercomputer Center of RAS. The authors are also grateful to Dr. V. Chashchikhin for the assistance in the construction of the silica gel topology and coordinates.

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Figure1 115x162mm (300 x 300 DPI)


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Figure2 80x80mm (600 x 600 DPI)



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Table of Contents Image 82x44mm (300 x 300 DPI)


Specific Interactions of Neutral Side Chains of an Adsorbed Protein

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