The geometry of hydrogen-bonds and carbonyl-carbonyl interactions between trans-amides in proteins and small molecules

Duddy, William John (2005) The geometry of hydrogen-bonds and carbonyl-carbonyl interactions between trans-amides in proteins and small molecules. PhD thesis, University of Glasgow.

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The geometries, at the level of atoms or groups of atoms, of interactions and motifs found in crystal structures in the Protein Data Bank (PDB) and the Cambridge Structural Database (CSD) are analysed. The bulk of the thesis examines electrostatic interactions that occur between trans secondary amide groups, or peptide groups as they are known in proteins. The two types considered are N-H-"O=C hydrogen-bonds and carbonyl-carbonyl interactions. Additionally, a chapter investigates specific hydrogen-bonded motifs, known as asx- and ST-tums, that commonly occur within protein structures. The geometry of hydrogen-bonds between trans secondary amide groups (i.e. peptide groups) has been studied extensively in proteins, and to a lesser extent in the CSD. They are a subset of the general case of N-H-O=C hydrogen-bonds. Previous analyses of the CSD have shown a tendency for N-H"-O=C hydrogen-bonds to exhibit lone-pair directionality, where the hydrogen atom is near to the plane of the lone-pairs of the carbonyl oxygen atom, and the H-O=C angle approaches 120°. For trans secondary amides the in-plane preference is also observed, but the H-''O=C angle is greater, averaging about 150°. Here, an examination of the CSD allows elucidation of four factors that together account for this difference in H-"O=C: 1. A smaller proportion of trans secondary amide carbonyl oxygens accept more than one hydrogen-bond than do carbonyl oxygens in general. 2. N-H"-O=C bonds often occur in 'ring' motifs with relatively constrained geometries and H"-O=C values near 120°. These cannot be formed by trans secondary amides. 3. Chains of hydrogen-bonds between trans secondary amides, with large H-O=C values, often extend throughout the crystal lattice. 4. The steric accessibility of trans secondary amide carbonyl oxygens is less than for carbonyl oxygens in general. It has been suggested that electrostatic interactions between carbonyl groups affect hydrogen-bond geometry in alpha-helix and beta-sheet, influence the twist of P-sheet, encourage polarization of carbonyl groups in alpha-helix, and explain the propensity of asparagine and aspartate residues in unusual regions of the Ramachandran plot. The carbonyl groups of ketones in the CSD frequently interact with each other, and commonly occur in three geometric motifs, that can be described as antiparallel, parallel, or perpendicular. At optimal geometry the antiparallel motif has energetic favourability approaching that of a medium-strength hydrogen-bond. Here it is shown that, after hydrogen-bonding has been taken into consideration, carbonyl-carbonyl interactions between trans secondary amides in the CSD also occur in these three motifs, and with a surprisingly similar propensity: 48% occur in the antiparallel arrangement (cf. 49% of those between ketones). Furthermore, interactions between main-chain carbonyl groups in a 454-chain subset of the PDB are identified. For each carbonyl-carbonyl interaction, its geometry, local secondary structure, and local hydrogen-bonding, are considered. The three motifs present in the CSD are not found to be representative of the geometries present in the PDB. However, other favourable carbonyl-carbonyl interaction motifs are observed. These occur in a variety of situations with respect to secondary structure and hydrogen-bonding, and are prevalent at the C-termini of alpha-helices. They are shown to contribute to the stability of common C-termini capping conformations, one being the Schellman loop, the other being the case where a proline terminates the helix. The hydrogen-bonded beta-turn is a small, well characterised, protein motif defined by a hydrogen-bond between the main-chain carbonyl group of one residue and the main-chain N-H group of another three residues ahead in the polypeptide chain. There are four common types, distinguished by geometry: I, I', II, and II'. In Asx- and ST-turns, the side-chain carbonyl of an asparagine, aspartate, serine, or threonine residue hydrogen-bonds with the main-chain N-H of a residue two ahead in the chain, such that they structurally mimic the beta-turn. Asx-turns have previously been categorized into four classes and ST-turns into three categories, based on side-chain rotamer types and the conformation of the central residue of each turn. Here it is shown that the four classes of asx-turn are geometrically equivalent to the four types of hydrogen-bonded beta-turn, and that the three categories of ST-turn are geometrically equivalent to three of the four types of hydrogen-bonded beta-turn. It is proposed that asx- and ST-turns be named using the type I, II, I' and II' beta-turn nomenclature. Using this nomenclature, the frequency of occurrence of both asx- and ST-turns is: type IF > type I > type II > type F, whereas for p-turns it is type I > type II > type F > type IF. It is found that the type II Asx- or ST-turn is the same as a previously identified hydrogen-bonded motif called the Asx- or ST-nest.

Item Type: Thesis (PhD)
Qualification Level: Doctoral
Keywords: Biochemistry.
Colleges/Schools: College of Medical Veterinary and Life Sciences
Supervisor's Name: Milner-White, Prof. James
Date of Award: 2005
Depositing User: Enlighten Team
Unique ID: glathesis:2005-71447
Copyright: Copyright of this thesis is held by the author.
Date Deposited: 10 May 2019 14:39
Last Modified: 03 Aug 2021 14:56

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