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Asian J Phys. Author manuscript; available in PMC 2015 March 12. Published in final edited form as: Asian J Phys. 2014 November ; 23(5): 735–744.

Ion binding to biological macromolecules Marharyta Petukh* and Emil Alexov Computational Biophysics and Bioinformatics Laboratory, Department of Physics, Clemson University, Clemson, SC 29634, USA

Abstract Author Manuscript

Biological macromolecules carry out their functions in water and in the presence of ions. The ions can bind to the macromolecules either specifically or non-specifically, or can simply to be a part of the water phase providing physiological gradient across various membranes. This review outlines the differences between specific and non-specific ion binding in terms of the function and stability of the corresponding macromolecules. Furthermore, the experimental techniques to identify ion positions and computational methods to predict ion binding are reviewed and their advantages compared. It is indicated that specifically bound ions are relatively easier to be revealed while non-specifically associated ions are difficult to predict. In addition, the binding and the residential time of non-specifically bound ions are very much sensitive to the environmental factors in the cells, specifically to the local pH and ion concentration. Since these characteristics differ among the cellular compartments, the non-specific ion binding must be investigated with respect to the sub-cellular localization of the corresponding macromolecule.

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Keywords ion binding; ion dependent reactions; biological macromolecules; electrostatics

1. Introduction

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Among all chemical elements in the periodic table, biological systems utilize only a few [3]. The analysis indicates that eleven chemical elements appear to be predominant in all biological systems. Four of them (O2−, H+, C and N3−) constitute 99.9 % of total number of atoms present in living organisms. Together with seven other elements (Na+, K+, Ca2+, Mg2+, P3−, S2− and Cl−), termed group I, they are considered to be essential or to be the basic components of organic structure. There are seventeen additional chemical elements such as V, Cr, Mn, Fe, Co, Ni, Cu, Zn, Mo, B, Si, Se, F, I, As, Br and Sn, termed group II, which are found in some living organisms but not in all. Most of these chemical elements are required for enzymatic activities, structural integrity, or simply provide screening of the electrostatic interactions in the water phase. Statistical studies indicate that 70% of all enzymes bind metal ions [4]. Metal ions are crucial for stabilizing proteins structure and hence, affect their function [4]. Therefore determining ions position in macromolecules is essential for understanding their structural and functional properties.

© Anita publications, All rights reserved. corresponding author [email protected].

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Four ions, Na+, K+, Mg2+ and Ca2+, are widely distributed in all living organisms [5]. Thus, Na+, K+ and Mg2+ are the major components of bodily fluids and the cytoplasma of the cells. The Mg2+ is the fourth most abundant element in vertebrates and the most abundant divalent cation within cells [6]. Thus about 60–65% of total Mg2+ are found in bone, about 35% in tissue compartments, and only about 1–2% in extracellular fluid including the plasma [7]. The Mg2+ is an integral component of chlorophyll and serves an essential function for photosynthesis as well [8]. Unlike Na+, Ca2+ and Cl−, which accumulate in extracellular milieu, Mg2+ is at least one order of magnitude more abundant inside the cell than in extracellular milieu. The same pattern holds for K+; hence, both Mg2+ and K+ are typically referred to as intracellular cations [8]. Since the intracellular concentrations of Na+ and Ca2+ are low, the metal binding chemistry of the nucleic acids in vivo is dominated by the more abundant K+ and Mg2+, but Mg2+ is found more frequently in binding to nucleic acids due to its double positive charge in comparison to K+ [8]. It was shown that approximately 90% of intracellular Mg2+ is bound to ribosomes or polynucleotides [9]. These facts indicate various roles of ions in structural stabilization of proteins, nucleic acid, and cell membranes.

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Among the group II chemical elements, Zn2+ is the second most abundant metal ion, after the iron, in all biological systems including microorganisms, plants, and animals [10]. Physiologically, approximately 98% of the total Zn2+ in an organism is found within the cell (40% in the nucleus and 50% in cytoplasm, organelles, and specialized vesicles), while the remaining is localized in the cell membrane [10]. The total Zn2+ concentration in eukaryotic cells was reported to be in the high micromolar range, with a concentration around 200 mM. The Zn2+ plays an important role in the structure of proteins and cell membranes. In some structural sites, it can be found either as a single metal ion or as part of a cluster of two or more ions, being coordinated only by amino acid residues with no bound solvent molecules. Structural Zn2+ sites have important implications for the functioning of metalloproteins. Interface Zn2+ sites can be defined in many proteins, where the Zn2+ ion bridges proteins or their subunits, thus playing an important role in the organization of the quaternary structure and/or active site.

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At the same time, ions can bind loosely (non-specifically) to the macromolecules or simply to be a mobile component of the water phase. As such they affect different aspects of physiological response such as signal transduction [11, 12], regulation of catalytic activity of enzymes [5], maintenance of osmotic balance [13] and the general ionic environment [5], and many others. It was shown that Na+, K+, Mg2+ and Ca2+ play significant role in transmission of nerve impulses and muscle contraction through trans-membrane concentration gradient [5, 14, 15]. Calcium in particular is known to be a ubiquitous second messenger that regulates a wide range of cellular processes [12, 16, 17]. Proteins function inside the solution with specific pH and temperature range, appropriate concentration of ions and small molecules around. Membrane proteins-transporters regulate ionic and osmotic balance inside cells as well as cells membrane permittivity for small molecules and ions. As an example, sodium activated potassium channel (Na+/K+-ATPase) catalyzes ATP-dependent transport of 3 ions of Na+ out of a cell in exchange for 2 K+ entering the cell [18, 19]. The (H+/K+)-ATPase is the transmembrane protein that transports

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protons out of cell in exchange for potassium ions entering the cell [20]. In all of these cases ions are involved in ionic and osmotic balance maintenance inside the cells. Thus ions can be found in biological system bound either specifically or non-specifically. Many macromolecules (proteins, DNA/RNA) bind ions specifically or nonspecifically as part of the active site or to stabilize the protein structure by creating or maintaining secondary/tertiary structure of macromolecules [21–24]. In many other cases, the ions are simply free charged particles existing in the water phase. For the purpose of this work, below we outline specific and non-specific ion binding separately. We also provide examples of such bindings and briefly discuss the available tools for determining or predicting binding sites.

2. Specific ion binding Author Manuscript

Specific ions binding occurs for most cases inside macromolecules and the ion is bound tightly to the macromolecule via various short-range forces including van der Waals (vdW) and others [25]. Frequently these ions participate in different types of enzymatic activities of the macromolecule.

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Among specifically bound ions, the Zn2+ ion is frequently tightly bound to proteins and it is considered an essential cofactor for hundreds of enzymes and thousands of metabolic and regulatory proteins providing two main roles: structural and regulatory (catalytic) [10, 24, 26]. In catalytic sites, Zn2+ ions participate directly in the catalytic process and generally exhibit a distorted tetrahedral geometry typically making three bonds to O, N, and S atoms while the forth one binds to a water molecule which in turn is frequently an activated nucleophile for the catalytic process [26]. Besides participating in catalytic activities of protein, specific bound Zn2+ ions also support protein stability. Thus, structural Zn2+ sites have important implications for the functioning of metalloproteins [27]. Zn-containing proteins are typically characterized by a Zn2+-centered tetrahedral coordination in which the metal ion is fully coordinated by four Cys residues via a thiolate group, or His residues usually in combination with Cys, forming “Zn finger” motifs (Figure 1) [10]. Binding of Zn2+ to tumor protein p53 conserves cysteinyl residues and by this mean stabilizes the tertiary structure of protein [28]. In some extracellular enzymes, occupation of calciumbinding sites involving surface loops leads to enhanced protein stability and provides protection against proteolytic digestion [29]. The Zn2+ also is known to stabilize the DNA double helix and control of gene expression [30].

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It was shown that intracellular regulatory proteins troponin C and calmodulin bind Ca2+ ions to a pair of cooperative binding sites [29]. This binding leads to conformational changes that modulate the activity of the target protein. Other enzymes have evolved to possess a Ca2+ binding site in which the Ca2+ ion plays an electrophilic role (electrophiles are positively charged species that are attracted to an electron rich center) in catalytic hydrolysis of substrates [29]. Many metal ions can exist stably in a number of different oxidation states. This allows these metals to participate in various types of oxidation-reduction processes [31]. One of the best examples of specific bound ions participating in enzymatic activities of proteins is hemAsian J Phys. Author manuscript; available in PMC 2015 March 12.

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containing proteins (Figure 2) [32]. Most copper-binding proteins are redox enzymes and electron-transport [33]. As an example, plastocyanin contains copper in its active center, which participates in photosynthesis dependent electron transfer [34].

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Manganese, copper and zinc ions act as Lewis acid (species that accept an electron pair) and constitute active sites of enzymes which catalyze reactions like hydrolysis, hydration, phosphorylation and carboxylation reactions [35]. The Mg2+ participates in the enzymatic reaction in two ways [5, 8]: as a cofactor (stabilizes a reaction intermediate; stabilizes a product leaving group; or binds two reactive substrates simultaneously and facilitate reaction through a proximity effect) or binds directly to enzymes. Thus, Mg2+ as well as Mn2+ ions are essential components of chlorophyll and assist photosynthesis. The Fe and Mb constitute the active sites of nitrogenase present in plants, which is responsible for nitrogen fixation [36]. Mo site exhibits approximate octahedral coordination geometry, while Fe – tetrahedral one [37]. The Mg2+ promotes specific structural or catalytic activities of proteins, enzymes or ribosomes [8]. Divalent ions (Mg2+ and Ca2+) are known to be crucial for ribozyme stability and activity [38]. The above examples show that specifically bound ions are tightly coordinated by a number of macromolecular atoms and thus can be considered to be part of macromolecular structure, or their binding can be considered to trigger a biochemical reaction. Typically the binding sites are very specific and recognize only one type of ion, which further manifest the importance of selectivity for various biological processes.

3. Non-specific binding Author Manuscript

Nonspecifically bound ions are typically found on the surface of macromolecules, where the long-range electrostatic interactions favors the binding [39]. Thus, it was shown that Ca2+ and Mg2+ ions nonspecifically bind to backbone phosphate oxygen atoms of nucleic acids [9, 40], which in turn reduces the electrostatic repulsion between phosphates, thereby stabilizing base pairing and base stacking [41, 42]. On the other hand, ions may freely drift as a “cloud atmosphere” around macromolecules. In most of cases these ions are functioning as cellular bulk electrolytes. The distribution of cationic ions inside cells is given in Table 1.

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The effect of bulk ions on the biophysical properties of macromolecules is a well-known fact. Many authors declared that protein binding affinity [43] and folding free energy strongly depend on bulk salt concentration [44]. Due to electrostatic effect rather than chemical (specific interactions), ions participate in the biopolymer reaction, Debye-Hückel potential screening, and the reduction in water activity at high salt concentrations due to its polarization [45]. The salt-dependence of protein-protein interactions has also been studied experimentally [46, 47] and proved with computation models [48–50]. Thus, experimentally it was shown that binding affinity of heterodimer proteins decreased in a solution with strong ionic strength. However, homodimer proteins show increased and decreased binding affinity with changing salt concentration depending on other properties of proteins [51].

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Different compartments of cells are characterized by their variety in salt concentration. The importance of this phenomenon supports the fact that macromolecule folding takes place in certain cell compartments, and strongly depends on salt concentration. The effect of salt concentration on folding state of macromolecules is demonstrated for RNA [52–55] and proteins [56–58]. In addition, the nonspecific bound ions affect signal transduction [11], maintenance of osmotic balance [13], and the general ionic environment [5].

4. Methods for predicting ion binding

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Methods that are used to determine ions position in proteins can be roughly divided into three groups: Methods based on direct experimental observations (X-ray crystallography, NMR); 3D macromolecule structure based methods that consider ions preferences to bind to the pocket with particular amino acids sequence, where the number of bounds that ions make with atoms in a cavity is equal to ions coordination number or valence; Computational methods that are based of energy calculations. These approaches are described in following section. 4.1. Experimental methods

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X-ray crystallography—The X-ray crystallography technique for macromolecular structure determinations requires obtaining macromolecule crystals [59]. Therefore to reveal the ion binding sites, the ions must be co-crystalized with the corresponding macromolecule, and thus to become part of its structure and practically immobilized. Because of that, X-ray crystallography can detect only tightly bound ions. Even in such cases, the detection is not trivial and many sites can be easily mislabeled as waters or may be missing entirely from fully refined crystal structures. For example, the identification of Na+ binding sites in protein crystals is complicated by the comparable electron density of this monovalent cation and water [60]. Besides difficulties in differentiating between ions, the functionally significant ions can also be easily mistaken for solvent molecules and vise verse. Nuclear Magnetic Resonance (NMR) spectroscopy—Nuclear magnetic resonance is one of the most successful and popular spectroscopic techniques in studying structures of macromolecules as well as the dynamic states of ions/metabolites in isolated living cells, tissues, etc (see review [61]).

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NMR is based on the physical phenomenon of atomic nuclei absorbing an external magnetic field. The effect depends on the strength of the magnetic field and the magnetic properties of the atom. Depending on the environment of atoms within macromolecules, the nuclei of individual atoms absorb different frequencies and this is used in the structure modeling. Information, accessible by NMR spectroscopy, allows one to analyze functional groups, bonds orientation and connectivity, and obtain the sequence and structure of macromolecules [62–64]. However, it should be mentioned that NMR technique has limitations, including the size of the macromolecule, the assumption about specific dynamics associated with the macromolecule and peaks overlapping (more details are provided in Ref. [65]). Assuming that these issues are resolved, the NMR can be used to determine the position of bond and free ions indirectly utilizing additional nuclei such

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as 1H, 19F, 31P, 13C, 15N, 23NA and 39K [61, 66]. Na+ and K+ ions can be observed directly due to their own resonance absorption. As in the case of X-ray crystallography, only immobilized ions can be determined by NMR spectroscopy. 4.2. In silico methods Once the 3D structure of a macromolecule is experimentally obtained, even if the ions cannot yet being identified the structure can still be used to predict ion positions. The predictions are typically based on the possibility of the ion to be coordinated by several amino acids. However, metal-binding sites in proteins are very diverse, varying in their coordination numbers [26, 67], geometries [68–72], metal preferences [73, 74], and ligands [75–77].

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There are numerous approaches for predicting the position of metal ions based on their preferences to a specific amino acid surrounding. Thus, since the Zn2+ and other transition metal ions are mostly bound by three or more amino acid residues at catalytic or structural sites, this can be used to identify putative specific Zn2+ binding. Having in mind that the amino acids coordinating the ions are almost always limited to four amino acid types - Cys, His, Glu, and Asp which ligate the metal ion through polar side chain atoms [71, 78], one can simply search for structural segments made of such amino acids. In addition, since it was demonstrated that different Zn2+ roles are associated with different bond distances and different amino acids surroundings in structural and catalytic sites [4], more specific predictions can be made. The coordination polyhedron of catalytic Zn2+ is usually dominated by histidine side chains, whereas that of structural Zn2+ is almost exclusively dominated by cysteine thiolates. Thus, catalytic and structurally important Zn2+ can in principle be distinguished. Additional factors that are considered in the predictions involve the observations that in most catalytic sites, water is found bound to Zn2+ as it transfers the least charge to Zn2+ and is less bulky compared to the protein ligands, enabling Zn2+ to serve as a Lewis acid in catalysis. In contrast, in most structural sites, more than two Cys are found bound to Zn2+, as Cys transfers the most charge to Zn2+ and reduces the Zn charge to such an extent that Zn2+ can no longer act as a Lewis acid; furthermore, steric repulsion among the bulky Cys(S−) prevents Zn2+ from accommodating another ligand [24].

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Calcium interacts with a very large number of proteins, but the variety of configurations of calcium-binding sites is rather limited. Despite the great diversity in the composition of ligand residues and bond angles and lengths of calcium-binding sites, structural analysis of calcium-binding sites in different classes of proteins has shown that common local structural parameters based on a set of geometric descriptions of the ideal pentagonal bipyramid geometry can be used to identify calcium-binding sites [79]. According to structural features of calcium-binding sites, proteins can be classified as EF-hand or non-EF-hand. Non-EFhand proteins, such as cell adhesion molecules, receptors, and transmembrane proteins, often have Ca2+-binding sites located at the linker regions between domains or at the exposed loop and turn regions between β-strands [75], and do not have conserved calcium-binding loops and flanked helices. The most common calcium-binding site in proteins is the EF-hand motif [80]. The classical EF-hand proteins have a helix-loop-helix motif characterized by a Asian J Phys. Author manuscript; available in PMC 2015 March 12.

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sequence of, usually, 12 residues. This sequence forms a loop that can accommodate calcium or magnesium with distinct geometries: magnesium is usually bound by six ligands in an octahedron, whereas seven ligands at the vertices of a pentagonal bipyramid coordinate calcium.

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Valence-based method—A straight forward and computationally fast algorithm is valence screening for metal ions [60]. This method is very effective to predict the position of metal ions that are completely buried inside the protein, but it gives inaccurate results while determining the position of nonspecific bound ions. Valence calculations are considered to be particularly accurate and ion-specific [81] because they exploit an empirical expression between the bond length and the bond strength of a metal ion–oxygen pair parameterized from results obtained in the extensive analysis of structures of metal oxides [82, 83]. The DOS program VALENCE is designed to calculate bond valences from bond lengths and vice versa. It can also calculate bond-valence sums and average bond lengths, and can determine bond-valence parameters from the bonding environments of different cations [84]. It was proved that valence calculations provide an accurate screening of water in protein crystals and may help identify Na+ binding sites of functional importance [60]. However, as far as this method relies on protein X-ray structure, valence number strongly depend on crystal structure resolution. Thus, the bond-valence approach is found to be more reliable for structures determined from high resolution data (1.5 A or better) [21].

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As an example, it was also demonstrated that it is possible to predict the location of Ca2+binding sites in proteins by taking into account local properties of the binding site. It appeared that the valence ≥1.4 was both necessary and sufficient to predict the location of bound Ca2+ ions [81]. Ca2+-binding sites in proteins have a coordination number anywhere between 3 and 8. Distances between Ca2+ and its ligands in the coordination shell vary from 1.6 Å to 3.3 Å. McPhalen et al. have also noted that, in general, Ca2+ does not lie in the plane of the ligand group [85].

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Sequence-based methods—Among other tools that rely on three-dimensional structure of proteins is CHED [86], which predicts transition metal-binding sites in apo-proteins based on geometric search of a triad amino acids composed of Cys, His, Glu, and Asp amino acids. SeqCHED [87] is a web-tool for predicting the metal binding sites of proteins from translated gene sequences based on remote homology templates with sequence identity between 18–100%. It also implements results from CHED. MetSite [88] involves sequence profile information in combination with approximate structural data. The MetSite server locates metal-binding regions in protein structures using a set of artificial neural network classifiers. The server uses secondary structure, solvent accessibility and distance matrices to improve the classification performance. MDB3 and MSDsite [89] use sequence comparison approach for identifying metalloprotein-binding site residues [90–92] refine predicted binding position based of binding free energy calculated with FoldX [93]. Energy/potential-based methods—The energetic properties of a biomolecule are determined by a combination of both short- and long-range forces. Short-range forces include several components, such as van der Waals, bonding forces, angular forces, and torsional interactions. Long-range forces, on the other hand, are typically dominated by Asian J Phys. Author manuscript; available in PMC 2015 March 12.

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electrostatic interactions. Because of their slow decay over distance, electrostatics cannot be neglected or truncated in biomolecular modeling; these forces contribute significantly to molecular interactions at all length scales [39]. One of the first attempts to determining energetically favorable binding sites on biologically important macromolecules belonged to Goodford [94]. In 1985 he proposed a new computational method called “GRID” that calculates the interaction of probes (water, the methyl group, amine nitrogen, carboxy oxygen, and hydroxyl) with proteins based on its surface energy distribution.

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The nonbonded interaction energy of the probe at each point on the GRID is calculated as the sum of different components such as energy, caused by Lennard-Jones potential; energy of electrostatic field; and energy of hydrogen bond formation. Each individual term in the summations relates to one pairwise interaction between the probe at position xyz and a single “extended” atom of the protein. Contours at negative energy levels define regions of attraction between probe and protein. The results of this algorithm might be used to determine ions position as well.

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Approaches utilizing hydrophobicity—Ions binding sites in proteins are varied in their coordination numbers and geometries, their metal preferences, and their ligands. While the “soft” metal Fe frequently bonds to sulfur ligands from the side chains of cysteine and methionine residues, there are few simple rules that describe the variety of bonding arrangements displayed by harder metals. But despite this variety, it was found that many metal sites in proteins share a common feature. Regardless of the metal and its precise pattern of ligation to the protein, there is a common qualitative feature to the bind site: the metal is ligated by a shell of hydrophilic atomic groups (containing oxygen, nitrogen, or sulfur atoms) and this hydrophilic shell is embedded within a larger shell of hydrophobic atomic groups (containing carbon atoms). It was proposed that the hydrophobicity contrast function may be useful for locating, characterizing, and designing metal binding sites in proteins [95]. In 1990 Eisenberg et al. pointed out that the environments of metal ions in proteins seemingly share a remarkable feature, “regardless of the metal and its precise pattern of ligation to the protein” [95]. The metal is coordinated by an inner sphere of hydrophilic groups, embedded in an outer sphere of hydrophobic groups, giving rise to a center of substantial hydrophobicity contrast. An algorithm based on calculation of the hydrophobicity contrast for the protein effectively locates ion-binding sites in a number of cases.

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BION web server—Usually the positions of nonspecific bound ions are on the surface of proteins. Because they do not exert a tight specific but rather loose interaction with protein, one may expect that the electrostatic attraction is strong enough to immobilize them. This hypothesis was tested and it was demonstrated that experimentally identified surface bound ions tend to be bound onto the protein surface at positions with strong potential but with polarity opposite to that of the ion (Figure 3) [96]. This observation was used to develop a method that uses a DelPhi-calculated potential map in conjunction with an in-house-

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developed clustering algorithm to predict nonspecific ion-binding sites. Because the method accounts for electrostatic interactions only, it supposedly is not sensitive to structural variations and fine details of the structure. Although this approach distinguishes only the polarity of the ions, and not their chemical nature, the nonspecific positively or negatively charged ions position was predicted with acceptable accuracy. The described algorithm was successfully implemented in user-friendly webserver, the BION web server [97], which addresses the demand for tools capable of predicting surface bound ions, for which specific interactions are not crucial and thus are very difficult to predict.

Acknowledgments The work was supported by a grant from NIH, NIGMS grant number R01GM093937.

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Author Manuscript Author Manuscript Author Manuscript Figure 1.

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Specific ion binding with respect to proteins stability (“zinc finger” domain from transcription factor sp1f2, PDB ID: 1sp2). Visualization was made with Chimera software [2].

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Author Manuscript Author Manuscript Figure 2.

Specific ion binding with respect to proteins catalytic activity (heme domain from hemoglobin, PDB ID: 1c7d). Visualization was made with Chimera software [2].

Author Manuscript Author Manuscript Asian J Phys. Author manuscript; available in PMC 2015 March 12.

Petukh and Alexov

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Author Manuscript Author Manuscript Author Manuscript Figure 3.

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Illustration of sharp potential well of the magnesium containing protein (protein ID 1ec0) with experimentally determined ion (yellow); and ion, being placed at predicted by BION position (lime). Visualization was made with VMD software [1]. Electrostatic field of protein is represented as “ForceField” lines, where red color represents area with negative potential and blue – with positive one.

Asian J Phys. Author manuscript; available in PMC 2015 March 12.

Petukh and Alexov

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Table 1

Author Manuscript

Distribution of cationic ions in cell (adapted from [6]). Ion

Total, mM

Free, mM

Na+

12

8

K+

140

120

Ca2+

3

0.0001

Mg2+

30

0.3

Author Manuscript Author Manuscript Author Manuscript Asian J Phys. Author manuscript; available in PMC 2015 March 12.

Ion binding to biological macromolecules.

Biological macromolecules carry out their functions in water and in the presence of ions. The ions can bind to the macromolecules either specifically ...
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