Structured conformation of biologically important molecules

Abstract

The thesis titled “Structure and Conformation of Biologically Important Molecules” consists of five chapters. The author has investigated the crystal and molecular structures of two cyclic dipeptides featuring the 2,5 diketopiperazine (DKP) ring system, with the aim of understanding the conformational flexibilities of cyclic dipeptides carrying different side chains. In addition, theoretical studies on the conformations of several cyclic dipeptides have been carried out via classical energy calculations. ________________________________________ Chapter 1 - Literature Survey A critical survey of the literature on the structure and conformation of cyclic dipeptides analysed by X ray diffraction is presented. The analysis covers eleven compounds reported so far. It is found that the diketopiperazine ring adopts either a planar or boat conformation. The DKP ring may buckle such that the C -C bond is either: • Equatorial (“bow spirit” conformation), or • Axial (“flag pole” conformation). Bond lengths show no significant variation, but bond angles vary depending on the ring buckling. An approximate relationship among the torsion angles within the DKP ring has been obtained. ________________________________________ Chapter 2 - Structure of Cyclo(L prolyl D phenylalanyl) The crystal and molecular structure of cyclo(L prolyl D phenylalanyl) is described. The compound crystallises in the monoclinic space group P2 , with unit cell dimensions: • a = 8.107 Å • b = 6.638 Å • c = 12.083 Å • = 96.43° • Z = 2 Using three dimensional intensity data, the structure was solved via direct methods. Key features: • DKP ring adopts a shallow boat conformation, with one C atom ~0.25 Å out of the least squares plane. • The molecule assumes a folded conformation ( (C ) = 75°), with the aromatic ring folded over the DKP ring. • The pyrrolidine ring shows an unusual conformation: atoms C and C deviate on opposite sides of the mean plane through the remaining ring atoms, rather than exhibiting a simple envelope form. Ideal conformational angles for a cyclo L prolyl grouping have been proposed. Packing features in the unit cell are also discussed. ________________________________________ Chapter 3 - Structure of Cyclo(L histidyl L aspartyl)·3H O The structure of cyclo(L histidyl L aspartyl) trihydrate was elucidated using 3D X ray data. The compound crystallises in orthorhombic P2 2 2 , with: • a = 17.040 Å • b = 14.150 Å • c = 6.040 Å • Z = 4 There are three water molecules of crystallisation. Initial Patterson interpretation using rigid groups (DKP, imidazole) was unsuccessful. The structure was solved using direct methods. Important structural features: • Molecule adopts a folded conformation, with the imidazole ring stacking over the DKP ring ( = 66.1°, = 108.8°). • Aspartyl side chain adopts an extended conformation ( = 72.3°). • The torsion angle (C -C -C -C ) of the aspartyl group is unusually large ( 50.5°), likely due to intermolecular hydrogen bonding. • The DKP ring is essentially planar, with both C atoms nearly coplanar. The crystal structure is stabilised by an extensive network of N–H···O and O–H···O hydrogen bonds. ________________________________________ Chapter 4 - Theoretical Conformational Analysis Empirical conformational energy calculations were carried out on several cyclic dipeptides to assess the influence of non bonded, electrostatic, and torsional interactions. The stable conformations of the following dipeptides were studied: • cyclo(L prolyl D phenylalanyl) • cyclo(glycyl L tryptophyl) • cyclo(L prolyl L leucyl) • cyclo(glycyl L aminobutyric acid) • cyclo(glycyl L histidyl) • cyclo(glycyl L aspartyl) The computed minimum energy conformations agree well with X ray and NMR observations. A rigorous conformational analysis of the DKP ring would require variation of all internal coordinates (bond angles at C , N, C ; peptide plane deviations). As a preliminary study, peptide units were constrained to be planar and rotated about the C –C vector while calculating energy components. The results show good agreement between theoretical minima and experimental conformations. ________________________________________ Chapter 5 - Influence of Hydrogen Bonding on Carboxylate Bond Lengths Accurate crystallographic data show that the two C=O bonds of a carboxylate group often differ significantly. In the structure reported in Chapter 2, the hydrogen bonded carbonyl shows a longer C=O distance. A comprehensive analysis of published amino acid and peptide structures reveals that hydrogen bonding systematically alters C=O bond lengths. Chapter 5 presents a quantitative relationship between the difference in hydrogen bond energies at the two oxygens and the difference in C=O bond lengths. ________________________________________ Appendix A brief description of the computer programs developed during the study is provided. ________________________________________ List of Publications (Reprints enclosed in the thesis.) 1. Effect of Hydrogen Bond on the Dimensions of the Carboxyl Group – E. Ramani & K. Venkatesan (1973), Indian Journal of Biochemistry and Biophysics, 10, 297. 2. Studies in Molecular Structure Symmetry and Conformation V: Conformation of the Disulphide Group – R. Srinivasan, K. K. Chakro, R. Ramani (1975), Current Science, 44, 331. 3. Theory of a Model System for Periodic Chemical Reactions Employing Successive Unimolecular Reactions – R. Ramani & G. N. Ramachandran (1972), Current Science, 41, 273. 4. Crystal Structure and Conformation of Cyclo(L prolyl D phenylalanyl) – R. Ramani et al. (1976), Acta Cryst., B32. 5. Crystal Structure and Conformation of Cyclo(L histidyl L aspartyl)·3H O. 6. Conformational Analysis of Cyclic Dipeptides by Theoretical Energy Calculation. (Items 2 and 3 were external work and are included only as supplementary material.)