Counterion effects in protein nanoparticle electrostatic binding: A theoretical study

Colloids and Surfaces B: Biointerfaces 128 (2015) 23–27

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Counterion effects in protein nanoparticle electrostatic binding: A theoretical study Goutam Ghosh ∗ UGC-DAE Consortium for Scientific Research, Mumbai Centre, Trombay, Mumbai 400085, India

a r t i c l e

i n f o

Article history: Received 20 November 2014 Received in revised form 5 February 2015 Accepted 8 February 2015 Available online 16 February 2015 Keywords: Protein folding energy Protein–nanoparticle electrostatic binding Counterion effects Dipole and induced-ion interactions Ion solvation in water

a b s t r a c t Effects of counterions on the folding conformation of proteins, bound electrostatically on the surface of charge-ligand functionalized nanoparticles, have been investigated based on the protein folding energy calculation. The folding energy of a protein has been taken as a sum of the short range interaction energies, like, the van der Waals attraction and the hydrogen bond energies, and the long range coulomb interaction energy. On electrostatic binding, counterions associated with surface ligands of nanoparticles diffuse into bound proteins through the medium of dispersion. As a result, bound proteins partially unfold, as observed in circular dichroism experiments, which has been realized using the “charge-dipole” and the “charge-induced dipole” interactions of counterions with polar and non-polar residues, respectively. The effect of counterions solvation in the dispersing medium, e.g., water, which causes water molecules to polarize around the counterions, has also been considered. The folding energy of bound proteins has been seen to decrease proportionally with the increasing number of diffusion of counterions and their polarizability. © 2015 Elsevier B.V. All rights reserved.

1. Introduction Study of the protein–nanoparticle interaction is important on the ground of applications of functional nanoparticles in medical therapies; e.g., drug delivery [1,2], magnetic resonance imaging (MRI) [3,4], hyperthermia treatment for tumor cells [5–7], and so on. Upon intra venous administration of nanoparticles, proteins get adsorbed at the nano-bio interface mediated by forces; like, solvation forces, hydrophobic attraction and electrostatic interactions; and thus form a dynamic ‘corona’ on the nanoparticle surface. These bound proteins may become biologically toxic. Therefore, the toxicity of nanoparticles is one of the major concerns for biomedical applications [8–10]. We have earlier reported [11–13] that chargeligand functionalized nanoparticles electrostatically bind with the oppositely charged proteins. As a result, counterions associated with the ligands on nanoparticle surface become “sterically” free to diffuse into bound proteins and unfold their secondary conformations. This sort of interaction model has been given a name by us as the “reverse-charge-parity counterions” or RCPC model [13]. Proteins are polypeptides of amino acids having well defined folding conformations and carrying a net surface charge depending on the pH of the dispersing medium. They fold spontaneously into complicated three-dimensional structures that are essential

∗ Tel.: +91 22 25594727. E-mail address: [email protected] http://dx.doi.org/10.1016/j.colsurfb.2015.02.015 0927-7765/© 2015 Elsevier B.V. All rights reserved.

for specific biological activities. Understanding the protein folding mechanisms helps to design and modify the novel proteins, to understand human degenerative diseases caused by protein misfolding and/or aggregation [14,15]. A number of different interactions define the protein folding conformations. These include hydrogen bonds, electrostatic interactions, van der Waals interactions and hydrophobic interactions [16,17]. As protein folds in an aqueous environment, contribution of a specific interaction depends on the difference between the interactions within the protein (interior) and the interaction of the protein with the adjacent water molecules (exterior). For example, both the hydrogen bonds and the van der Waals interactions occur within the folded protein, as well as between the solvent molecules and the protein residues. On the other hand, both the electrostatic and the hydrophobic interactions have significant contributions within the protein and play specific roles in the folding of proteins [18]. Therefore, the stability of a protein solution depends on several factors, like, the macromolecular net charge, the solvent pH, the chemical nature of the dissolved ions [19], and so on. The ion binding with protein residues changes its folding conformation. For example, binding of Ca2+ ion to the transglutaminase causes an increase of its radius of gyration, indicating the unfolding of the protein [20,21]. Binding sites of the metal ions in a protein are varied in their coordination numbers and geometries, their metal preferences, and their ligands (which include backbone carbonyl oxygen; side chain groups and water molecules) [22,23]. Yamashita et al. [24] have reported that the metal ions generally bind in the

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regions of high hydrophobicity contrast in proteins which is due to the fact that the electron distributions in the metal ions are highly symmetric, attracting the electron-pair donors (Lewis bases) around the ion in a shell. In proteins these electron-pair donors are oxygen, nitrogen, and sulfur atoms. Interactions of metal ions with the carboxylic and the carboxamide groups in protein structures have also been reported [25,26]. Protein surfaces are far from uniform, consisting rather of an intricate network of polar and nonpolar groups to which salt ions have widely different affinities. For example, large anions are attracted to the hydrophobic interfaces (Hoffmeister effect) via the surface modified solvation and the polarization [27,28]. Direct ion-pairing [29] between salt particles and charged surface groups also give rise to ion specific phenomena [30]. Protein design presents a demanding task for a potential energy function. The energy produced by design potentials is intended to correlate with the free energy of protein folding. The force field also must be compatible with the computational requirements of protein design. For example, energy terms must be pair wise decomposable. In this work, the folding energy of native proteins has been calculated based on interactions involving the van der Waals force between polar and non-polar residues, the hydrogen bonding between polar residues, and the electrostatic attraction between charged residues [16]. Aim of this work was to calculate the change in the folding energy of proteins, on electrostatic binding with the charge-ligand functionalized nanoparticles and subsequent diffusion of counterions, leading to their partial unfolding [11–13]. This is the first theoretical work using the RCPC interaction model [13], between charged proteins and oppositely charge-ligand functionalized nanoparticles, which has explained possible mechanisms of unfolding of bound proteins due to the diffusion of counterions. 2. Method and calculations 2.1. Protein folding energy 2.1.1. van der Waals energy The most significant packing force of folding of a protein involves the short range van der Waals potential between both polar and non-polar residues. This potential provides a physical basis for the side chain packing specificity, thereby supporting the native-like folded state with well-organized cores, and is given by the Lennard–Jones 12-6 expression [16], EvdW =

 D   r 12 0 0 4εεo

r

 r 6 

−2

0

(1)

r

where r is the distance between the center of a pair of interacting atoms (within polar and/or non-polar residues) and the center of the protein core, and has been computed using the protein specific atomic coordinates obtained from different protein data banks. r0 is the equilibrium radii of the core and D0 is the depth of the potential well which was taken 8 kJ in the present calculations. ε and εo are the dielectric constants of water (=78.4) and vacuum (=1), respectively. In the present calculation, it was assumed that the van der Waals interaction between non-polar residues would be equivalent to the hydrophobic interaction, as the later one also varies inversely with 6th power of r [11]. 2.1.2. Hydrogen bond energy The energy, EHB , of hydrogen bonding (H-bond) between polar residues of a protein is given by [16] EHB =

 D    r 12 0 0 4εεo

5

r

 r 10 

−6

0

r

F()

(2)

The expression for F() depends on the type of hybridization used in donor and acceptor atoms. In this calculation, sp3 –sp3 hybridization was taken into consideration (for simplicity) which gives, F() = cos4  [16]. As the average over angular distributions, = 1/3, we get, F() = 1/9. Note that the contribution of this term appears in designing the helical surfaces [31]. 2.1.3. Electrostatic energy The electrostatic interaction arises due to the charge residues in protein and is not strong enough to compensate for the energy of desolvation [32]. It only maintains the specific folding of protein, and its functional interactions [33,34]. A simple form of the electrostatic energy, EES , is given by the distance-attenuated Coulomb interaction term [16],

  Qi Qj 

EES = 322.0637

ij

4εεo rij

(3)

where Q’s are charges of ith and jth atoms separated by a distance rij which can be calculated using the coordinates of respective atoms. Contribution of this term to the total protein folding energy is significant only when the charged atoms are in close proximity. It is to be noted here that close to the charge surface of protein the water molecules are polarized, and a favorable interaction between water dipoles and protein charge maintains the stability of protein dispersion. 2.2. Protein–nanoparticle RCPC interaction and counterions effects As mentioned earlier, contribution of the electrostatic interaction to protein folding is not significant. On electrostatic binding with the charge-ligand functionalized nanoparticle, charge residues of proteins can no longer maintain their specific folding conformation. In addition, counterions associated with the surface ligands of nanoparticles get condensed around protein surface, further assisting the diffusion of counterions into the protein interior. As a result, folding energy due to the van der Waals interaction (Eq. (1)) and the hydrogen bonding (Eq. (2)) would reduce. Counterions in the interior of protein would, on the other hand, develop attractive interactions with both polar and non-polar residues. As a result of these attractive interactions of protein residues with external agents, like counterions, would reduce the intra-protein short range interactions. In addition, the counterion solvation in water would cause the adjacent water molecules to take polarized structure changing the dielectric constant and entropy of the dispersing medium. Therefore, the solvation of counterions may cause several effects, like, the reduction of hydrophobicity, the breaking of hydrogen bonds, etc. Details of these effects have been discussed below. If a counterion of charge q lies at a distance r from the center of a polar residue of dipole moment  and dipolar length l, the corresponding attractive coulomb energy, Edip , can be given by [35] Edip = −

nq cos  n(ze) =− 4εεo r 2 4εεo r 2

(4)

where n represents the number of counterions interacting with the polar residues, z is the valency of counterions, e is the elementary charge.  is the angle between the dipole and the line joining the counterion to the center of the dipole. For attractive interaction,  = 0◦ . Again, the energy, Eind , of attraction between the counterions and the non-polar residues of bound proteins can be given by [35] Eind = −

n˛(ze)2 2(4εεo )2 r 4

(5)

G. Ghosh / Colloids and Surfaces B: Biointerfaces 128 (2015) 23–27

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(violet dots) diffusing into the bound proteins. This binding can be described by the following expression: Protein (native) + ligand-nanoparticle → Protein–ligand-nanoparticle

Scheme 1. Cartoon showing the RCPC interaction between proteins and a nanoparticle.

where ˛ is the polarizability of counterions, diffusing into bound proteins. Of course, effects of these coulomb interactions, in general, would be much more complex which has been avoided in the present calculation. When small ions are dispersed in water, shells of the polarized water molecules are formed around dissolved counterions [35]. These shells constitute the waters of solvation or hydrations of counterions, i.e., counterions are solvated or hydrated. The radius of the hydrated layer around a counterion would vary with its size or polarizability as well as with the polarizability of water, and it is not limited to the molecules directly in contact with counterions, but transmitted to molecules in second, third, etc. layers [35]. The region of enhanced structuring in water is referred to as the solvation zone around the counterions. This solvation effect can have a number of important consequences, like, changing the dielectric constant, the conductivity, and the density of the dissolving medium, causing the reduction of hydrophobicity in the protein core and, in turn, breaking the hydrogen bonds between protein residues. This energy expression, Ewp , is given by [35]

(7)

The interaction of HEWL has been considered with the negative charge-ligand functionalized nanoparticles (since, pI > pH). Negative charge-ligands could be tri-lithium citrate, tri-sodium citrate, tri-potassium citrate, and tri-magnesium citrate as owners of positive counterions, e.g., Li+ , Na+ , K+ and Mg2+ , respectively [12]. Similarly, the interaction of ALA has been considered with the positive charge-ligand functionalized nanoparticles (since, pI < pH) where positive charge-ligands could be cetylpyridinium chloride, cetylpyridium bromide, and cetylpyridium iodide as owners of negative counterions, e.g., Cl− , Br− and I− , respectively [13]. According to the RCPC model, proteins and ligand-nanoparticles with same charge (either positive or negative) will repel each other [11,12]. In the present calculation, the polarizability (which increases with ionic size) and the number of counterions were considered as the factors which affect the folding energy of proteins, bound with ligand-nanoparticles (Eq. (7)). The ratio (R) between the folding energy of the bound proteins to that of the native proteins (as given in Eq. (7)) was derived. This ratio of calculated folding energies has been compared with the ratio (R) between the ␣-helix content in the bound proteins to that in the native proteins, measured experimentally using the circular dichroism technique [12,13]. The folding energy was calculated in SI units and was obtained as −19.671 kJ mol−1 and −29.913 kJ mol−1 , respectively, for the native state of HEWL and ALA, indicating the native folding energy of ALA is greater than that of HEWL. 3. Results

2.3. Calculations

In Fig. 1, experimental and theoretical R values have been shown with the polarizability (in A˚ 3 ) values of counterions, diffusing into the bound proteins: (A) HEWL and (B) ALA in solutions with constant protein-to-nanoparticle ratio. The filled circles (•) (open circle () for Mg2+ ) show the theoretical R values and the filled triangles () (open triangle () for Mg2+ ) show the experimental R values with respective error bars [12,13]. These error bars were derived from the ␣-helix contents obtained by analyzing three CD spectra, using the CDNN 2.1 program [11–13], of each protein–nanoparticle solution. The experimental R values have been scaled with the theoretical values for comparison purpose. It is to be mentioned here that the counterions’ number, in the present calculation, was considered proportional to the nanoparticle concentration, as taken in

In the present work, interaction of two different proteins, e.g., hen egg white lysozyme (HEWL, M.W. ∼ 14,300 g mol−1 , pI 11) and ␣-lactalbumin (ALA, M.W. ∼ 14,200 g mol−1 , pI 5.7), with the charge-ligand functionalized nanoparticles have been considered. The atomic coordinates of HEWL and ALA were obtained from the protein data bank (PDB) files, e.g., 193L [36] and 1A4V [37], respectively. Charged residues usually lie at the outer surface of a protein. Non-polar residues lie around the core and polar residues lie between the core and the surface of a protein. Therefore, any change in the core environment would cause unfolding of a protein. On the other hand, change in the exterior environment of proteins will affect their dispersibility in the medium. The RCPC (reverse-charge-parity counterions) model of interaction between the charged proteins and the opposite charge-ligand functionalized nanoparticles has been shown by the cartoon in Scheme 1. It shows the electrostatic binding of proteins with the charged ligands (brown) on a nanoparticle (black sphere). Arrows show counterions

Fig. 1. Calculated (䊉, ) and experimental (, ) values of the folding ratio (R) of bound and native proteins, (A) HEWL and (B) ALA, as a function of the polarizability of diffusing counterions. The error bars in experimental R values were derived from the ␣-helix contents obtained by analyzing three CD spectra, the using CDNN 2.1 program [11–13], of each protein–nanoparticle solution.

Ewp = −

n(∝ ·∝w ) 4εεo r 6

(6)

where ˛w (=0.148 A˚ 3 ) is the polarizability of water molecules, and r is the radius of solvation of counterions.

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G. Ghosh / Colloids and Surfaces B: Biointerfaces 128 (2015) 23–27

Table 1 Calculated and experimental values of R of HEWL for different counterions. The error bars in experimental R values were derived from the ␣-helix contents obtained by analyzing three CD spectra, using the CDNN 2.1 program [11–13], of each protein–nanoparticle solution. Counterions

Valency

R (calculated)

R (experimental)a , b

Li+ Na+ K+ Mg2+

1 1 1 2

0.984 0.944 0.801 0.949

0.980 0.932 0.865 0.940

a b

± ± ± ±

0.08 0.01 0.10 0.08

0.2 has been added with each value for scaling with calculated R values. Values taken from Ref. [12] and recalculated.

Table 2 Calculated and experimental values of R of ALA for different counterions. The error bars in experimental R values were derived from the ␣-helix contents obtained by analyzing three CD spectra, using the CDNN 2.1 program [11–13], of each protein–nanoparticle solution. Counterions −

Cl Br− I−

Valency

R (calculated)

R (experimental)a

1 1 1

0.972 0.962 0.942

0.975 ± 0.08 0.963 ± 0.01 0.944 ± 0.10

a Values taken from Ref. [13] and recalculated. No scaling was required to match with calculated values.

experiment. Theoretical and experimental values of R for HEWL and ALA interacting with different charge-ligand counterion nanoparticles have been shown in Tables 1 and 2, respectively. Close matching between the theoretical and the experimental R values certainly indicates the validity of the folding energy terms and the counterion–protein interactions terms used in the present calculation. The theoretical R with counterions’ number have been shown for HEWL, bound with negative charge-ligand-functionalized nanoparticles, in Fig. 2(A) and for ALA, bound with positive chargeligand-functionalized nanoparticles, in Fig. 2(B). R shows by open circles () for Li+ and Cl− (in Fig. 2(A) and (B), respectively), by open triangles () for Na+ and Br− (in Fig. 2(A) and (B), respectively), by open squares () for K+ and I− (in Fig. 2(A) and (B), respectively), and by filled circles (•) for Mg2+ (in Fig. 2(A)).

Fig. 2. Calculated values of the folding ratio (R) of bound and native proteins, (A) HEWL and (B) ALA, as a function of diffusing counterions’ number for Li+ and Cl− (), Na+ and Br− (), K+ and I− (), and Mg2+ (䊉).

4. Discussion Comparing Fig. 1(A) and (B), it is clear that the positive counterions affect more strongly on folding conformation of bound proteins as compared to the negative counterions. This result agrees with the fact that the positive (metal) ions, being smaller in size, are spherical and have tendency of binding with the hydrophobic core of bound proteins [24], in contrast to the negative ions which are bigger in size and are expected to be non-spherical. As mentioned in an earlier section that the short range interactions, like, the van der Waals and the hydrophobic interactions in the hydrophobic core are the main folding energies of a protein. Therefore, the diffusion of positive counterions in the hydrophobic core has caused stronger unfolding of bound proteins as compared to negative counterions. It is also clear that the unfolding increases with increasing the polarizability (˛) and the valency (for example, see Mg2+ point in Fig. 1(A)) of counterions. On the contrary, though negative counterions have larger size and higher polarizability, and can polarize associated water molecules more strongly destroying more number of H-bonds, but their effect on the total folding energy of bound proteins is weaker than positive metal ions, as the hydrophobic core of bound proteins is very little affected in this case. In Fig. 2, we can see that theoretical R has decreased with increasing the number of counterions which is in agreement with the decrease of experimental R with increasing concentration of functional IONP [12,13]. Decreasing R or increasing unfolding of bound proteins with increasing the counterions’ number indicates that more number of polar and non-polar residues of bound proteins were affected by increasing the number of the ion-dipole and the ion-induced dipole interactions. This result suggests that the counterions acted as the agents in modulating the protein core energy. It is to be mentioned here that the electrostatic binding between the proteins and the charge-ligand nanoparticles causes modification in the favorable interaction (mentioned in an earlier section) between the charge residues of proteins and the adjacent water molecules. As a result, the dispersibility of proteins will be affected causing the proteins to bind with functional nanoparticles, in addition to the electrostatic binding. This effect would also cause the condensation of counterions around protein surface helping them to diffuse into the interior of bound proteins. But this phenomenon will not affect the protein folding energy calculation. The present work suggests the possible origins of the unfolding of proteins bound electrostatically with the charge-ligand functionalized nanoparticles [11–13], in terms of the interactions of counterions with different protein residues and the solvation of counterions in water. Energy-wise the counterion–protein residue interactions can be ordered as, ion–dipole interaction > ioninduced dipole interaction > ion solvation interaction. This work also shows that without counterion diffusion, folding energy of bound proteins would remain the same as that of the native proteins which is in agreement with our experimental observations of the interaction of proteins with the ‘aged’ charge-ligand functionalized nanoparticles [11–13]. The entire calculation was based on the concept of the RCPC interaction model which may offer several useful applications in biomedicine. In this context, our latest paper on interaction between the human hemoglobin and charge-ligand counterion IONP can be refered [38]. In this paper, we have reported that even the hydrophobic binding of human hemoglobin with the positive charge-ligand counterion IONP has caused unfolding of hemoglobin conformation. This was due to the diffusion of thermally excited negative counterions into hemoglobins bound within the proximity limit.

G. Ghosh / Colloids and Surfaces B: Biointerfaces 128 (2015) 23–27

5. Conclusions The effects of counterions’ diffusion through water medium into proteins, electrostatically bound with the opposite charge-ligand functionalized nanoparticles, have been investigated in terms of the folding energy of proteins. The folding energy of native proteins has been calculated using various energy terms involving the van der Waals, the hydrogen bond and the electrostatic interactions. On the electrostatic binding of proteins with the charge-ligand functionalized nanoparticles, the intra-protein electrostatic interaction term becomes insignificant. As a result, the favorable interaction between the charge residues of proteins and the water molecules would reduce causing the counterions to condense around the protein surface and forcing them to diffuse into the bound proteins. Counterions diffused in the hydrophobic core of the bound proteins would develope attractive interactions with both polar and non-polar residues, and as a result, the intra-protein van der Waals interaction energy as well as the H-bonding energy would reduce. The solvation of counterions would polarize and orient water molecules around them causing the protein folding van der Waals energy and the hydrogen bond energy to reduce. All these effects, as result of counterions’ diffusion, would unfold the secondary conformations of the bound proteins. The protein folding energy was seen to reduce with increasing the polarizability, the charge and the number of counterions. The present theoretical results agree well with our earlier experimental results indicating the validity of the RCPC model of the protein–nanoparticle interaction, as well as the formulations used for counterion–protein interactions in the present investigation. References [1] R. Langer, Nature 392 (1998) 5. [2] C. Alexiou, W. Arnold, R.J. Klein, F.G. Parak, P. Hulin, C. Bergemann, W. Erhardt, S. Wagenpfeil, A.S. Lubbe, Cancer Res. 60 (2000) 6641. [3] H.B. Na, J.H. Lee, K. An, Y.I.I. Park, M. Park, I.S. Lee, D.-H. Nam, T.S. Kim, S.-H. Kim, S.-W. Kim, K.-H. Lim, K.-S. Kim, S.-O. Kim, T. Hyeon, Angew. Chem. Int. Ed. 46 (2007) 5397.

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