Molecular Modeling of Ions in Biological Systems

Ions are ubiquitous in biological systems. Metal ions contribute to biological function as counter ions, as triggers to cellular response, and as catalytic cofactors. They play structural roles and are part of the catalytic active site of metalloenzymes. NH4+ ions provide a source of nitrogen for amino acid synthesis in plants and bacteria and help maintaining the acid-base balance in mammals. The cationic side chains of amino acids Lys and Arg contribute to the stability of proteins and protein-DNA complexes through cation–π interactions with the π electrons of aromatic amino acids.
\nDeveloping molecular models for ion-protein interactions is required to investigate and understand the various biological functions of ions and to complement and interpret experimental data. In this regard, the aims of this thesis are to: 1- Investigate the selectivity of alkali ions toward N, O, and S-containing ligands (a step toward understanding protein selectivity to metal ions). 2- Optimize new semiempirical quantum mechanical models for calcium and magnesium metalloproteins. 3- Study the strength and directionality of cation–π interactions involving inorganic and organic cations interacting with model compounds of aromatic amino acid side chains in both gas phase and aqueous solution. 4- Investigate the selectivity and binding affinity of AmtB and RhCG ammonium transport proteins toward various ions and study the function of amino acids that line the transport pathway of these proteins.
\nProteins bind metal ions through N, O, and S atoms from the side chains of the amino acids His, Asp, Glu, Ser, Tyr, Asn, Gln, Cys, and Met and from main chain carbonyl and amino groups. NH3, H2O, and H2S are used as minimal models for N, O, and S ligands to investigate the selectivity of alkali metal ions. Polarizable potential models for NH3 and H2S that accurately reproduce the experimental properties of the pure and aqueous liquids are developed. The models are used, together with a previously developed model for water, to study the solvation structures and solvation free energies of the ions in the pure liquids and to investigate the selectivity of alkali ions toward the three ligands. The models yield solvation structures and solvation free energies in good agreement with experiments and show a selectivity of alkali ions toward the three ligands that follows the order H2O > NH3 > H2S.
\nMagnesium and Calcium are two of the most bioavailable metals and are known to play roles in signal transduction and in muscular contraction and are cofactors in many enzymes. Semiempirical models are optimized for the two metals based on the ab initio structures and binding energies of complexes formed between Mg2+ and Ca2+ with ligands that model binding groups in biological and chemical systems. Optimized models are tested on the ab initio properties of ~170 ion-ligand binary and ion-water-ligand ternary complexes. Optimized models of Mg underestimate the binding energies of S-containing complexes but give structures and binding energies of other complexes in agreement with ab initio data. Models for Ca reproduce the ab initio properties of all complexes, including S complexes.
\nCation–π interactions are common among protein structures and are believed to play key roles in stabilizing proteins and protein complexes with ligands and DNA. Polarizable potential models for the interaction of Rb+, Cs+, Tl+, ammonium, tetramethylammonium, and tetraethylammonium with aromatic amino acid side chains are calibrated based on the ab initio properties of the different cation–π complexes. The models are used to study the binding affinity and complexation geometry of the different pairs in water. Results are showing that cation–π interactions persist in aqueous solutions and are stronger than charge-dipole interactions (such as interactions of Rb+, Cs+, Tl+ with ethanol and acetamide). It is also found that cation–π complexes have geometries in aqueous solution similar to gas phase. In addition, results suggest that cation–π interactions influence the solubility of aromatic compounds in aqueous solutions.
\nProteins of the Amt/Mep/Rh family —ammonium transporters (Amt) in plants and bacteria, methylamine permease (Mep) in yeast, and rhesus (Rh) blood-group associated glycoproteins in animals— facilitate the permeation of ammonium across cell membranes. Crystal structures of AmtB and RhCG proteins reveal structural differences along the transport pathways. Amt proteins are selective toward NH4+ over Na+ and K+, yet their activity can be inhibited by ions such as Cs+ and Tl+. Polarizable potential models for NH3, NH4+, Na+, K+, Rb+, Cs+, and Tl+ interacting with model compounds to side chains of amino acids that line the transport pathway are optimized. The models are used to calculate the binding affinity of both proteins toward the various ligands and to study the functional roles of amino acids along the transport pathway. Results show that among the various ligands, only Cs+ and Tl+ can compete with NH4+ for binding the two proteins and hence inhibit the protein activity. Results also show that the large hydrophobicity of the pore lumen in RhCG protein destabilizes NH4+ and water molecules in the pore which suggests a net NH3 transport mechanism of the protein.

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