Conformation of Biological Molecules

The determination of the three-dimensional structure of a biological molecule is the starting point in the understanding of molecular mechanisms involved in its complex biochemical reactions. The molecular architecture of multimolecular systems such as membranes and chromosomes provides the key to the fascinating field of molecular biology. Stereochemical details of biological macromolecules and their interactions with pharmacological agents form the basis for drug design. Naturally, the study of the structure and function of biological molecules has aroused tremendous interest and investigations in this area are being carried out in a large number of laboratories. The techniques used for this purpose include both experimental methods (X-ray and neutron diffraction measurements, study of NMR, ESR, vibrational and electronic spectra, ORD, CD and dipole moment measurements, biochemical modifications etc. ) and the­ oretical methods (quantum mechanical and classical potential energy calculations, Monte­ Carlo simulations and molecular graphics). F or several years now, X-ray diffraction [1] has served as our only source of infor­ mation on the three-dimensional arrangements of atoms in biopolymers. Fiber-diffrac­ tion of DNA led to the proposal of the DNA double helix. Fibers of long~hain polymers show ordering in the direction of the fibre-axis but not in the transverse plane. Accurate estimates of the dimensions of helical structures can be made using techniques on the basis of which models of biopolymers can be constructed.

Contenu

1 General Theory.- 1.1 Introduction.- 1.2 What is Conformation?.- 1.3 Conformational Theory.- 1.4 Structure of Long-Chain Polymers.- 1.5 Problems in NMR Studies of Biological Molecules.- 1.5.1 1H-NMR.- 1.5.2 2H-NMR.- 1.5.3 13C-NMR.- 1.5.4 15N-NMR.- 1.5.5 31P-NMR.- 1.5.6 Other Nuclei.- 2 NMR Techniques in Conformational Studies.- 2.1 Coupling Constants.- 2.2 Chemical Shifts of Hydrogen-Bonded Protons.- 2.3 Magnetic Anisotropy of Chemical Bonds or Groups.- 2.4 13C Chemical Shifts.- 2.5 31P Chemical Shifts.- 2.6 Relaxation Times (T1 and T2).- 2.7 Nuclear Overhauser Effect.- 2.8 Paramagnetic Reagents.- 2.9 Use of Liquid Crystals as Solvents.- 2.10 Deuterium Quadrupole Coupling Constants.- 2.11 Solvent Accessibility.- 2.12 From NMR Parameters to Spatial Structures.- 3 Nucleosides, Nucleotides and Nucleic Acids.- 3.1 Description of Nucleotide Structures.- 3.2 Glycosidic Bond Rotations.- 3.3 Sugar Ring Conformation: Pseudorotation.- 3.4 Backbone Angles.- 3.4.1 Torsion Angles ø ?.- 3.4.2 Angles ø?.- 3.4.3 Angles ??.- 3.4.4 Torsion Angles ??, ?.- 3.5 NMR Studies on Nucleosides.- 3.6 Small Nucleotides.- 3.6.1 2?-, 3?- and 5?-Mononucleotides.- 3.6.2 Cyclic Nucleotides.- 3.6.3 Pyridine Nucleosides and Nucleotides.- 3.6.4 5?-Di- and Triphosphates.- 3.7 Dinucleoside Phosphates and Short Segments of Nucleic Acids.- 3.8 Random-Coil Polynucleotides.- 3.8.1 Oligo- and Polyribonucleotides.- 3.8.2 Deoxyribonucleotides.- 3.9 Helical Polynucleotides.- 3.10 t-RNA.- 3.11 Drug-Nucleic Acid Interactions.- 4 Amino Acids, Peptides and Proteins.- 4.1 Description of the Structure of Peptide Units.- 4.2 Theoretical Considerations. The ø, ? Maps.- 4.3 NMR Techniques in the Study of Peptide Conformations.- 4.3.1 cis-trans Isomerization (Angle ?).- 4.3.2 ø and ? Angles.- 4.3.3 Side-Chain Conformations.- 4.3.4 Detection of N-H...O=C Hydrogen Bonds.- 4.3.5 Molecular Symmetry.- 4.3.6 Conformational Mobility.- 4.3.7 1H and 13C Chemical Shifts.- 4.4 Conformations of Amino Acids.- 4.5 Linear Peptides.- 4.5.1 Dipeptides.- 4.5.2 Tripeptides.- 4.5.3 Tetrapeptides.- 4.5.4 Pentapeptides.- 4.5.5 Hexapeptides.- 4.5.6 Larger Peptides. Peptide Hormones.- 4.5.6.1 Angiotensin.- 4.5.6.2 Leuteinizing Hormone-Releasing Hormone (LRF).- 4.5.6.3 Peptides Containing a-Aminobutyric Acid (Aib).- 4.5.6.4 Human Parathyroid Hormone (PTH).- 4.5.6.5 Insulin.- 4.6 Cyclic Peptides.- 4.6.1 Dipeptides.- 4.6.2 Tripeptides.- 4.6.3 Tetrapeptides.- 4.6.4 Pentapeptides.- 4.6.5 Hexapeptides.- 4.6.6 Larger Cyclic Peptides, Peptide Hormones and Antibiotics.- 4.6.6.1 Oxytocin and Vasopressin.- 4.6.6.2 Gramicidin S.- 4.6.6.3 Valinomycin.- 4.7 Homopolymeric Peptides. Helix-Coil Transition.- 4.8 Characterization of Protein Structures by NMR.- 4.8.1 Spatial Arrangement of Atoms in the Molecules.- 4.8.2 Protein Mobility.- 4.8.3 Enzyme - Substrate Binding.- 4.8.4 Thermodynamic Parameters.- 4.8.5 Conformation of Specific Proteins.- 4.8.5.1 Lysozyme.- 4.8.5.2 Basic Pancreatic Trypsin Inhibitor (BPTI).- 4.8.5.3 Dihydrofolate Reductase.- 4.8.5.4 Antibody Combining Site.- 4.8.5.5 Myelin Basic Protein (MBP).- 4.8.5.6 Calcium-Binding Proteins.- 4.8.5.7 Elastin and Tropoelastin.- 4.8.5.8 Ribonuclease.- 4.8.5.9 Hemoproteins and Hemoenzymes.- 4.8.5.10 Collagen.- 4.8.5.11 ?-Chymotrypsin.- 4.9 Protein-Nucleic Acid Interaction.- 4.9.1 Specificity.- 4.9.2 Nature of Intermolecular Forces.- 4.9.3 Applications.- 5 Polysaccharides.- 5.1 Structures of Polysaccharides and Carbohydrates.- 5.2 Conformations of Monosaccharides.- 5.3 Conformations of Polysaccharides.- 5.4 Glycoproteins and Peptide-Carbohydrate Interactions.- 6 Lipids and Molecular Organization in Membranes.- 6.1 Biomembranes.- 6.2 General Properties of Phospholipids.- 6.3 Conformations of Phospholipids.- 6.3.1 Conformations of the Glycerol Moiety.- 6.3.2 Conformations in the ?-Chains.- 6.3.3 Conformations in the ? and ? Chains.- 6.4 Membrane Organization and Fluidity.- 6.4.1 Fluidity.- 6.4.1.1 Rotational Motions.- 6.4.1.2 Lateral Diffusion on the Surface of the Membrane.- 6.4.1.3 Flip-Flop Motions.- 6.4.2 Determination of Organization.- 6.4.2.1 31P-NMR.- 6.4.2.2 2H-NMR.- 6.4.2.3 Other Studies.- 6.5 Lipid-Protein and Lipid-Cholesterol Interactions.- 7 Acknowledgements.- 8 References.- 9 Appendix.- 10 Subject Index.