Pallela, Ramjee

English

Open Access Repository of Indian Theses

AbstractAb initio (HF, MP2, and CCSD(T)) and DFT (B3LYP) calculations were done in modeling the cation (H+, Li+, Na+, K+, Ca+2, Mg+2, NH4+ and NMe4+) interaction with aromatic side chain motifs of four amino acids viz. phenylalanine, tyrosine, tryptophan and histidine. As the metal ion approaches the -framework of the model systems, they form strongly bound cation- complexes, where the metal ion is symmetrically disposed with respect to all ring atoms. In contrast, proton prefers to bind covalently to one of the ring carbons. The NH4+ and NMe4+ ions have shown NH interaction and CH… interaction with the aromatic motifs. The interaction energies of NH… and CH… complexes are higher than hydrogen bonding interactions and thus the orientation of aromatic side chains in protein is effected in the presence of ammonium ions. However, the regioselectivity of metal ion complexation is controlled by the affinity of the site of attack. In the imidazole unit of histidine the ring nitrogen has much higher metal ion (as well as proton) affinity compared to the -face, facilitating the in-plane complexation of the metal ions. The interaction energies increase in the order of 1-M < 2-M < 3-M < 4-M < 5-M, for all the metal ion considered.  Similarly, the complexation energies with the model systems decrease in the following order: Mg+2 > Ca+2 > Li+ > Na+  > K+  NH4+ > NMe4+.  The energy decomposition analysis performed by block localized wavefunction – energy decomposition (BLW-ED) method indicates that the interaction of these  systems with metal cations is characterized by contributions from polarization energy, electrostatic energy and charge-transfer energy, with the contribution of the first being dominant. Charge transfer energies contribute in significant proportions, in fact more than the electrostatic energy contribution in many cases. The polarization energy contribution is superior to others (60-80%), followed by charge transfer (20-30%) in case of the proton affinities of the aromatic complexes at various sites, The results obtained in this analysis are in contrast with the earlier energy decomposition schemes, as the contribution of charge transfer is competing with the electrostatic contribution. The variation of the bond lengths and the extent of charge transfer upon complexation correlate well with the computed interaction energies.The cooperativity of the two significant non-covalent interactions viz. cation interactions is demonstrated quantum mechanically, and with the aid of database analyses. It is observed that, subtle  interactions become substantial in the presence of a metal ion, and the cooperativity results in mutual stabilization. Quantum chemistry calculations have revealed that the  - interactions, which are traditionally considered as subtle, with a range of 2-4 kcal/mol, will be substantial, ranging up to 17-18 kcal/mol in the presence of a metal ion. The metal ions have higher affinity towards a  dimer compared to a single -moiety. This is further substantiated with the large occurrence of M- motifs in both CSD and PDB.  In the course of action, the possible interactions between cation and the -moiety of the aromatic residues present in all the proteins of Protein Data Bank (PDB) are evaluated and stored as a publicly available web-based database cation-aromatic database (CAD). All the metal ions and protonated basic amino acid residues are considered as cations. The motifs are defined on the basis of distance between the cation and the centroid of the aromatic ring.  Of these pairs, those having the cation within a cylinder with the arene ring as a base are identified. This geometric criterion enables the identification of strong cation- interactions. CAD is freely accessible via the Internet at http://203.199.182.73/gnsmmg/databases/cad/. The present chapter addresses the apparent disparity in the structural parameters of the X-ray structures and theoretical models of cation-π complexes in biological and chemical recognition. Hydrated metal ion (Li+, Na+, K+, Mg+2, Ca+2) complexes with benzene (cation-π) are considered as model systems to perform quantum mechanical calculations in evaluating the geometrical parameters and interaction energies of these complexes. The computations disclose that there is a variation in the structural parameters as well as in the interaction energies of these complexes with the multiple additions of water molecules. The distance between the cation and the π-system increases with the addition of water molecules, delineating the influence of solvent or the neighborhood atoms on the structural parameters of cation-π systems present in crystal structures.The chapter describes a comprehensive database named, Protein Ligand Interaction Database (PLID), created with 6,295 ligands bound to proteins extracted from the Protein Data Bank (PDB). This is by far the most comprehensive database of physico-chemical properties, quantum mechanical descriptors and the residues present in the active site of proteins. Datamining analysis performed using decision tree, random forest and neural network techniques on the binding pockets reveals that the binding preference of a given ligand to a set of proteins is guided by certain combinations of amino acid residues present at the binding site. Further, it is found that the function of enzymes can also be correlated to the binding site residues. It is a publicly available web-based database at http://203.199.182.73/gnsmmg/databases/plid/.

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http://eprints.csirexplorations.com/107/1/Abstract.doc

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