• Saraswathi Vishveshwara

      Articles written in Journal of Chemical Sciences

    • Effect of the valine-threonine constraint on the dynamics of the proline helix — A molecular dynamics study

      S Shobana Gautham Nadig Saraswathi Vishveshwara

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      Proline residues in helices play an important role in the structure of proteins. The proline residue introduces a kink in the helix which varies from about 5° to 50°. The presence of other residues such as threonine or valine near the proline region can influence the flexibility exhibited by the kinked helix, which can have an important biological role. In the present paper, the constraint introduced by threonine and valine on a proline helix is investigated by molecular dynamics studies. The systems considered are (1) a poly-alanine helix with threonine-proline residues (TP) and (2) a poly-alanine helix with valine-threonineproline residues (VTP), in the middle. Molecular dynamics simulations are carried out on these two systems for500 ps. The results are analyzed in terms of structural transitions, bend-related parameters and sidechain orientations.

    • Binding of active site directed ligands to phospholipase A2: Implications on the molecular constraints and catalytic mechanism

      K Seshadri Saraswathi Vishveshwara Mahendra K Jain

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      Molecular constraints for the localization of active site directed ligands (competitive inhibitors and substrates) in the active site of phospholipase A2 (PLA2) are characterized. Structure activity relationships with known inhibitors suggest that the head group interactions dominate the selectivity as well as a substantial part of the affinity. Theab initio fitting of the amide ligands in the active site was carried out to characterize the head group interactions. Based on a systematic coordinate space search, formamide is docked with known experimental constraints such as coordination of the carbonyl group to Ca2+ and hydrogen bond between amide nitrogen and ND1 of His48. An optimal position for a bound water molecule is identified and its significance for the catalytic mechanism is postulated. Unlike the traditional “pseudo-triad” mechanism, the “Ca-coordinated-oxyanion” mechanism proposed here invokes activation of the catalytic water to form the oxyanion in the coordination sphere of calcium. As it attacks the carbonyl carbon of the ester, a near-tetrahedral intermediate is formed. As the second proton of the catalytic water is abstracted by the ester oxygen, its reorientation and simultaneous cleavage form hydrogen bond with ND1 of His48. In this mechanism of esterolysis, a catalytic role for the water co-ordinated to Ca2+ is recognised.

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