Ions, binding to proteins

Figure 14,12 Phosphoinositide cascade. The cleavage of phosphatidyl inositol 4,5-bisphosphate (PIP ) into diacyiglycerol (DAG) and inositol 1,4,5-trisphosphate (IP5) results in the release of calcium ions (due to the opening of the IP3 receptor ion channels) and the activation of protein kinase C (due to the binding of protein kinase C to free DAG in the membrane). Calcium ions bind to protein kinase C and help facilitate its activation.

When an action potential approaches the axon terminal, voltage-gated Ca2+ channels (N-type) open and Ca2+ enters the presynapse. Ca2+ ions bind to proteins that connect the synaptic vesicle with the plasma membrane (acronym SNAP), inducing membrane fusion and consequently exocytosis of the neurotransmitter into the synaptic cleft. Botulinum b toxin contains a specific protease which interferes with synaptobrevin (a vesisle protein which interacts with the SNAP proteins) so that vesicles cannot fuse any longer. The inhibition of acetylcholine release can thus cause paralysis and death. 

We have applied this method in our QM/MM implementation [176] to the study of ion solvation and the mechanisms of selectivity in ion channels or ion-coupled transporters. Ion selectivity has been extensively studied at the MM level with both classical and polarizable force fields. However, classical simulations may be compromised by their inability to account for charge transfer and electronic polarization, thought to be critical for ion binding to proteins. We have extended QM/ MM FEP to studies of Na /K solvation and selectivity by water clusters with... 

II. Studies of halide ion binding to proteins or other molecules where an artificial metal label is attached. 

PonER, N. Rogniaux, H. Chevreux, G. Van Dorsselaer, A. Ligand-metal ion binding to proteins Investigation by Esi mass spectrometiy. Methods Enzymol. 2005, 402. 361-389. 

Such free radicals may be stabilized by binding to proteins. Redox reactions may also occur between ionic species, for example the oxidation of reduced cytochrome c by hexacyanoferrate (ferricyanide) ions. 

This receptor-mediated endocytotic pathway has been especially well studied in the uptake of iron from blood plasma. Iron, because of its very low-solubility product (< 1(T17 at pH 7.4), is transported in plasma bound to the iron-binding protein transferrin. Two Fe3+ ions bind to each transferrin molecule. Entry into... 

J. Baudier and D. Gerard, Ions binding to S100 proteins Structural changes induced by calcium and zinc on SlOOa and SlOOb proteins, Biochemistry 22, 3360-3369 (1983). 

Copper ions bind to and inhibit many enzymes. Of more importance, perhaps, is that in free solution or when bound to proteins, copper ions catalyse the Fenton reaction which produces the highly dangerous hydroxyl radical, OH (Appendix 9.6). 

The intracellular concentrations are total — the free concentration of some ions, such as Ca and phosphate, is much lower in the cytosol of the cell due to binding to proteins or compartmentation. For example, the free concentration of Ca ions in the cytosol is approximately 0.1 pmol/L. The concentration of phosphate in the cytosol is approximately 1 mmol/L. Most of the Ca ions in the cell are present in the endoplasmic reticulum (see Chapter 13). 

Fig. 8. An example of the lack of strong interaction between Ca ions bound to proteins and a-helix dipoles. Shown is the double-Ca -binding site of thermolysin (3TLN), with two associated helices (residues Gly-136 to Asn-181). Side chains are drawn only for Asp-138 and Glu-177 (thick lines), two Ca -ligand residues from the helical regions. Only main-chain atoms are shown for other residues. The Ca ions are circles. The positive amino terminus of the dipole from the first helix passes to one side of the Ca positions. The negative carboxy terminus of the dipole from the second helix bypasses the Ca positions at some distance. The only interaction between the ions and the helices is with the side chains of Asp-138 and Glu-177 that protrude from their respective helix axes.

In addition to enthalpic contributions, the entropy effects accompanying protein-metal ion interactions are substantial. These effects manifest themselves in the desolvation of the metal ion and its binding site. However, as the metal ion binds to a protein, the entropy gain of solvent release may be offset to some degree by the reduction of the conformational entropy of the polypeptide chain as it becomes more firmly bound... 

The low molecular weight L-histidine nickel complex can cross biological membranes (Sarkar 1984). How nickel gets inside of cells may determine the effects of the nickel compounds. If nickel ions are taken into the cytosol and bind to protein, they are not delivered to the nucleus, which prevents the interaction of nickel ions with DNA. Crystalline nickel compounds are phagocytized and nickel ions are delivered to the nucleus where they interact with DNA or DNA protein complexes (Costa 1995). 

Ca2+ binding to proteins is generally considered to be weak relative to that of the transition metal ions. As is predictable for a hard metal ion the coordination appears to be entirely through O donor atoms, from carboxyl and peptide O atoms (see Table 11). Unfortunately Ca2+ is spectroscopically silent and much of the work on the elucidation of its binding sites relies upon the specific... 

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