- NSF-PAR ID:
- 10336810
- Date Published:
- Journal Name:
- Physical Chemistry Chemical Physics
- Volume:
- 24
- Issue:
- 22
- ISSN:
- 1463-9076
- Page Range / eLocation ID:
- 13571 to 13586
- Format(s):
- Medium: X
- Sponsoring Org:
- National Science Foundation
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Flory’s random coil model assumes that conformational fluctuations of amino acid residues in unfolded poly(oligo)peptides and proteins are uncorrelated (isolated pair hypothesis, IPH). This implies that conformational energies, entropies and solvation free energies are all additive. Nearly 25 years ago, analyses of coil libraries cast some doubt on this notion, in that they revealed that aromatic, but also β-branched side chains, could change the 3J(HNHCα) coupling of their neighbors. Since then, multiple bioinformatical, computational and experimental studies have revealed that conformational propensities of amino acids in unfolded peptides and proteins depend on their nearest neighbors. We used recently reported and newly obtained Ramachandran plots of tetra- and pentapeptides with non-terminal homo- and heterosequences of amino acid residues to quantitatively determine nearest neighbor coupling between them with a Ising type model. Results reveal that, depending on the choice of amino acid residue pairs, nearest neighbor interactions either stabilize or destabilize pairs of polyproline II and β-strand conformations. This leads to a redistribution of population between these conformations and a reduction in conformational entropy. Interactions between residues in polyproline II and turn(helix)-forming conformations seem to be cooperative in most cases, but the respective interaction parameters are subject to large statistical errors.more » « less
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Phosphorylation and dephosphorylation of proteins by kinases and phosphatases are central to cellular responses and function. The structural effects of serine and threonine phosphorylation were examined in peptides and in proteins, by circular dichroism, NMR spectroscopy, bioinformatics analysis of the PDB, small-molecule X-ray crystallography, and computational investigations. Phosphorylation of both serine and threonine residues induces substantial conformational restriction in their physiologically more important dianionic forms. Threonine exhibits a particularly strong disorder-to-order transition upon phosphorylation, with dianionic phosphothreonine preferentially adopting a cyclic conformation with restricted φ (φ ~ –60 ̊) stabilized by three noncovalent interactions: a strong intraresidue phosphate-amide hydrogen bond, an n→π* interaction between consecutive carbonyls, and an n→σ* interaction between the phosphate Oγ lone pair and the antibonding orbital of C–Hβ that restricts the χ2 side chain conformation. Proline is unique among the canonical amino acids for its covalent cyclization on the backbone. Phosphothreonine can mimic proline's backbone cyclization via noncovalent interactions. The preferred torsions of dianionic phosphothreonine are φ,ψ = polyproline II helix > α-helix (φ ~ –60 ̊); χ1 = g–; χ2 ~ +115 ̊ (eclipsed C–H/O–P bonds). This structural signature is observed in diverse proteins, including in the activation loops of protein kinases and in protein-protein interactions. In total, these results suggest a structural basis for the differential use and evolution of threonine versus serine phosphorylation sites in proteins, with serine phosphorylation typically inducing smaller, rheostat-like changes, versus threonine phosphorylation promoting larger, step function-like switches, in proteins.more » « less
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The conformational preferences of 28 sterically and electronically diverse N-aryl amides were detd. using d. functional theory (DFT), using the B3LYP functional and 6-31G(d) basis set. For each compd., both the cis and trans conformers were optimized, and the difference in ground state energy calcd. For six of the compds., the potential energy surface was detd. as a function of rotation about the N-aryl bond (by 5° increments) for both cis and trans conformers. A natural bond orbital (NBO) deletion strategy was also employed to det. the extent of the contribution of conjugation to the energies of each of the conformers. By comparing these computational results with previously reported exptl. data, an explanation for the divergent conformational preferences of 2° N-aryl amides and 3° N-alkyl-N-aryl amides was formulated. This explanation accounts for the obsd. relationships of both steric and electronic factors detg. the geometry of the optimum conformation, and the magnitude of the energetic difference between cis and trans conformers: except under the most extreme scenarios, 2° amides maintain a trans conformation, and the N-bound arene lies in the same plane as the amide unless it has ortho substituents; for 3° N-alkyl-N-aryl amides in which the alkyl and aryl substituents are connected in a small ring, trans conformations are also favored, for most cases other than formamides, and the arene and amide remain in conjugation; and for 3° N-alkyl-N-aryl amides in which the alkyl and aryl substituents are not connected in a small ring, allylic strain between the two N-bound substituents forces the aryl substituent to rotate out of the plane of the amide, and the trans conformation is destabilized with respect to the cis conformation due to repulsion between the π system of the arene and the lone pairs on the oxygen atom of the carbonyl. The cis conformation is increasingly more stable than the trans conformation as electron d. is increased on the arene because the more electron-rich arenes adopt a more orthogonal arrangement, increasing the interaction with the carbonyl oxygen, while simultaneously increasing the magnitude of the repulsion due to the increased electron d. in the π system. The trans conformation is favored for 2° amides even when the arene is orthogonal to the amide, in nearly all cases, because the C-N-C bond angle can expend at the expense of the C-N-H bond angles, while this is not favorable for 3° amides.more » « less
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Abstract Binuclear alkyne manganese carbonyls of the type (RC≡CR')Mn2(CO)
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