Coulombic attractions between partially chargedmain-chain atoms stabilise the right-handed twist found in most β-strands

Maccallum, Peter H.; Poet, Ron; Milner‐White, E. James

doi:10.1016/s0022-2836(95)80057-3

Cited by 49 publications

(30 citation statements)

References 37 publications

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“…In this respect too, Pro is favoured because its carbonyl moiety is a particularly good H-bond acceptor and it holds on tenaciously to its hydration shell, even when placed in a hydrophobic environment. The conformation is further stabilised by dipolar interactions along the backbone between N-H and carbonyl moieties so that they form a 3-residues per turn helix (Maccallum, Poet, & Milner-White, 1995). Gln residues are also frequently found in the PP-II conformation which they may sometimes stabilise by forming a side-chain-tobackbone H-bond between residues i and i+1 (Adzhubei, Sternberg, & Makarov, 2013; Unfolded proteins are usually less hydrophobic and more highly charged than globular proteins so they do not readily self-associate (Uversky, Gillespie, & Fink, 2000).…”

Section: Caseins Are Unfolded Proteinsmentioning

confidence: 99%

Casein structures in the context of unfolded proteins

Thorn

Ecroyd

Carver

et al. 2015

International Dairy Journal

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Caseins were among the first proteins to be recognised as functional but unfolded. Many others are now known, providing better models of casein behaviour than either detergents or folded proteins. Caseins are members of a paralogous group of unfolded phosphoproteins, some of which share the ability to sequester amorphous calcium phosphate through phosphate centres. Non-covalent interactions of caseins can be through Pro-and Gln-rich sequences. Similar sequences in other unfolded proteins can also form open and highly hydrated structures such as gels, mucus and slimes. Many unfolded proteins, including κ-and αS2-caseins, can form amyloid fibrils under physiological conditions. The sequence-specific interactions that lead to fibrils can be reduced or eliminated by low specificity interactions among a mixture of caseins to yield, instead, amorphous aggregates. The size of amorphous whole casein aggregates is limited by the C-terminal half of κ-casein whose sequence resembles that of a soluble mucin. Disciplines Medicine and Health Sciences | Social and Behavioral Sciences

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Section: Caseins Are Unfolded Proteinsmentioning

confidence: 99%

Casein structures in the context of unfolded proteins

Thorn

Ecroyd

Carver

et al. 2015

International Dairy Journal

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“…Maccallum et al (1995) based their conclusions on an analysis of terminally blocked alanine (''alanine dipeptide''). As we have shown in this paper, the individual strands display a very small bias towards right-hand twisting, whereas double and triple-stranded b-sheets show a strong energetic preference for a right-handed twist.…”

Section: Comparison With Earlier Studiesmentioning

confidence: 99%

“…In a recent study on model antiparallel alanine b-sheets, Yang & Honig (1995) emphasized optimization of van der Waals' interactions and hydrogen bonding geometries as responsible for the right-handed twist of the b-sheets. In another recent study, based on the conformational energy of terminally blocked alanine, Maccallum et al (1995) suggested that the intra-strand electrostatic interactions between adjacent carbonyl groups along a polypeptide backbone contribute important stabilization of the righthanded twist of b-sheets.…”

Section: Introductionmentioning

confidence: 99%

“…These previous energetic studies were limited by several factors, including: (1) consideration of rigid models of minimized conformational energy (Chou et al, , 1983aMaccallum et al, 1995), without inclusion of entropic contributions; (2) construction of static sheet models from individual chains without equilibration via dynamics (Yang & Honig, 1995), which led to large fluctuations in conformational energies for different twists and difficulty in determining the optimal twists of the sheets; and (3) analysis of the alanine dipeptide (Chothia, 1973;Maccallum et al, 1995), which is an inadequate model with which to interpret the stability of b-sheets (see below).…”

Section: Introductionmentioning

confidence: 99%

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Molecular Simulations of β-Sheet Twisting

Wang

O’Connell

Tropsha

et al. 1996

Journal of Molecular Biology

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“…Recently, we have been able to determine the free interaction enthalpy between a C-F and a CϭO bond dipole ranging between Ϫ0.8 kJ mol Ϫ1 and Ϫ1.2 kJ mol Ϫ1 (2,3). Despite the evident importance of orthogonal interactions between carbonyl dipoles for crystal packing (4-9), peptide secondary structure (10)(11)(12), and medicinal chemistry (13), no experimental quantification of the energetic contributions of such interactions has been reported so far. Intermolecular perturbation theory (IMPT) calculations performed by Allen et al (9) assessed the interaction energy for a perpendicular propan-2-one dimer at an optimal contact distance of d O⅐ ⅐ ⅐CϭO ϭ 3.02 Å to amount to Ϫ7.6 kJ mol Ϫ1 , comparable to the strength of weak hydrogen bonds.…”

mentioning

confidence: 99%

Orthogonal dipolar interactions between amide carbonyl groups

Fischer

Wood

Allen

et al. 2008

Proc. Natl. Acad. Sci. U.S.A.

119

109

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Orthogonal dipolar interactions between amide C‫؍‬O bond dipoles are commonly found in crystal structures of small molecules, proteins, and protein-ligand complexes. We herein present the experimental quantification of such interactions by employing a model system based on a molecular torsion balance. Application of a thermodynamic double-mutant cycle allows for the determination of the incremental energetic contributions attributed to the dipolar contact between 2 amide C‫؍‬O groups. The stabilizing free interaction enthalpies in various apolar and polar solvents amount to ؊2.73 kJ mol ؊1 and lie in the same range as aromatic-aromatic C-H⅐ ⅐ ⅐ and -interactions. High-level intermolecular perturbation theory (IMPT) calculations on an orthogonal acetamide/Nacetylpyrrole complex in the gas phase at optimized contact distance predict a favorable interaction energy of ؊9.71 kJ mol ؊1 . The attractive dipolar contacts reported herein provide a promising tool for small-molecule crystal design and the enhancement of ligand-protein interactions during lead optimization in medicinal chemistry.mutant cycle ͉ protein folding ͉ torsion balance ͉ medicinal chemistry D ipolar contacts involving organic bond dipoles and a carbonyl group, or a pair of carbonyl groups are commonly found both in chemistry and biology (1). On the basis of an analysis of crystal structures of small molecules, proteins, and protein-ligand complexes, it is theorized that, owing to steric constraints, these dipoles preferentially adopt an orthogonal alignment at closest contact distance (Fig. 1). For their expected weakness, the contributions of these interactions have previously been neglected in the study of inter-and intramolecular contacts. Recently, we have been able to determine the free interaction enthalpy between a C-F and a CϭO bond dipole ranging between Ϫ0.8 kJ mol Ϫ1 and Ϫ1.2 kJ mol Ϫ1 (2, 3). Despite the evident importance of orthogonal interactions between carbonyl dipoles for crystal packing (4-9), peptide secondary structure (10-12), and medicinal chemistry (13), no experimental quantification of the energetic contributions of such interactions has been reported so far. Intermolecular perturbation theory (IMPT) calculations performed by Allen et al. (9) assessed the interaction energy for a perpendicular propan-2-one dimer at an optimal contact distance of d O⅐ ⅐ ⅐CϭO ϭ 3.02 Å to amount to Ϫ7.6 kJ mol Ϫ1 , comparable to the strength of weak hydrogen bonds. To provide experimental proof for the favorable energetic contributions attributed to orthogonal dipolar carbonylcarbonyl interactions, we embarked on their determination. We chose to investigate a monomolecular model system, based on the Wilcox molecular torsion balance (14-16), providing for the determination of weak interactions with a greater accuracy and geometric control than given by the study of bimolecular chemical or biological complexes. The primary noncovalent interaction, an aromatic-aromatic edge-to-face C-H⅐ ⅐ ⅐ contact, prearranges the functional groups bearing the i...

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Coulombic attractions between partially chargedmain-chain atoms stabilise the right-handed twist found in most β-strands

Cited by 49 publications

References 37 publications

Casein structures in the context of unfolded proteins

Casein structures in the context of unfolded proteins

Molecular Simulations of β-Sheet Twisting

Orthogonal dipolar interactions between amide carbonyl groups

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