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High-resolution crystal structures of protein helices reconciled with three-centered hydrogen bonds and multipole electrostatics.

Kuster DJ, Liu C, Fang Z, Ponder JW, Marshall GR - PLoS ONE (2015)

Bottom Line: The reason why they have been overlooked by structural biologists depends on the small crankshaft-like changes in orientation of the amide bond that allows maintenance of the overall helical parameters (helix pitch (p) and residues per turn (n)).The Pauling 3.6(13) α-helix fits the high-resolution experimental data with the minor exception of the amide-carbonyl electron density, but the previously associated backbone torsional angles (Φ, Ψ) needed slight modification to be reconciled with three-atom centered H-bonds and multipole electrostatics.Thus, a new standard helix, the 3.6(13/10)-, Némethy- or N-helix, is proposed.

View Article: PubMed Central - PubMed

Affiliation: Department of Biomedical Engineering, Washington University, St. Louis, MO, United States of America.

ABSTRACT
Theoretical and experimental evidence for non-linear hydrogen bonds in protein helices is ubiquitous. In particular, amide three-centered hydrogen bonds are common features of helices in high-resolution crystal structures of proteins. These high-resolution structures (1.0 to 1.5 Å nominal crystallographic resolution) position backbone atoms without significant bias from modeling constraints and identify Φ = -62°, ψ = -43 as the consensus backbone torsional angles of protein helices. These torsional angles preserve the atomic positions of α-β carbons of the classic Pauling α-helix while allowing the amide carbonyls to form bifurcated hydrogen bonds as first suggested by Némethy et al. in 1967. Molecular dynamics simulations of a capped 12-residue oligoalanine in water with AMOEBA (Atomic Multipole Optimized Energetics for Biomolecular Applications), a second-generation force field that includes multipole electrostatics and polarizability, reproduces the experimentally observed high-resolution helical conformation and correctly reorients the amide-bond carbonyls into bifurcated hydrogen bonds. This simple modification of backbone torsional angles reconciles experimental and theoretical views to provide a unified view of amide three-centered hydrogen bonds as crucial components of protein helices. The reason why they have been overlooked by structural biologists depends on the small crankshaft-like changes in orientation of the amide bond that allows maintenance of the overall helical parameters (helix pitch (p) and residues per turn (n)). The Pauling 3.6(13) α-helix fits the high-resolution experimental data with the minor exception of the amide-carbonyl electron density, but the previously associated backbone torsional angles (Φ, Ψ) needed slight modification to be reconciled with three-atom centered H-bonds and multipole electrostatics. Thus, a new standard helix, the 3.6(13/10)-, Némethy- or N-helix, is proposed. Due to the use of constraints from monopole force fields and assumed secondary structures used in low-resolution refinement of electron density of proteins, such structures in the PDB often show linear hydrogen bonding.

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Related in: MedlinePlus

The potential surface near helical torsional angles for Ac-Ala-Ala-Ala-NMe as calculated by QM.The red line traces the transition between the two energy minima-like conformers without an activation energy barrier.
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pone.0123146.g018: The potential surface near helical torsional angles for Ac-Ala-Ala-Ala-NMe as calculated by QM.The red line traces the transition between the two energy minima-like conformers without an activation energy barrier.

Mentions: To further characterize these potential surfaces, the locations of the activation energy required for transitions between minima were tabulated. On the contour plots, both QM and the monopole force fields show potential funnels with two minima-like positions. From the contour plots for all the potential surfaces, no energy barrier existed between the two minima, and a “U” shape path would lead the structure from the higher energy position to the lower energy one without any activation-energy barrier (Fig 18). By QM calculations, the minimum energy-like conformer by QM was located at ϕ = -70, ψ = -17, while the other conformer was found at φ = -73, ψ = -33. The first was close to the classic 310-helix and the second closer to the “dynamic” helix. Thus, they approximate the 310 and α-helix regions, respectively. This suggests that the 310-helix was energetically the most stable structure for Ac-Ala-Ala-Ala-NHMe in vacuo. This is plausible since the more compact hydrogen-bonding pattern of the 310-helix allows one more hydrogen bond than the α-helix for the same length of peptide [64].


High-resolution crystal structures of protein helices reconciled with three-centered hydrogen bonds and multipole electrostatics.

Kuster DJ, Liu C, Fang Z, Ponder JW, Marshall GR - PLoS ONE (2015)

The potential surface near helical torsional angles for Ac-Ala-Ala-Ala-NMe as calculated by QM.The red line traces the transition between the two energy minima-like conformers without an activation energy barrier.
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4403875&req=5

pone.0123146.g018: The potential surface near helical torsional angles for Ac-Ala-Ala-Ala-NMe as calculated by QM.The red line traces the transition between the two energy minima-like conformers without an activation energy barrier.
Mentions: To further characterize these potential surfaces, the locations of the activation energy required for transitions between minima were tabulated. On the contour plots, both QM and the monopole force fields show potential funnels with two minima-like positions. From the contour plots for all the potential surfaces, no energy barrier existed between the two minima, and a “U” shape path would lead the structure from the higher energy position to the lower energy one without any activation-energy barrier (Fig 18). By QM calculations, the minimum energy-like conformer by QM was located at ϕ = -70, ψ = -17, while the other conformer was found at φ = -73, ψ = -33. The first was close to the classic 310-helix and the second closer to the “dynamic” helix. Thus, they approximate the 310 and α-helix regions, respectively. This suggests that the 310-helix was energetically the most stable structure for Ac-Ala-Ala-Ala-NHMe in vacuo. This is plausible since the more compact hydrogen-bonding pattern of the 310-helix allows one more hydrogen bond than the α-helix for the same length of peptide [64].

Bottom Line: The reason why they have been overlooked by structural biologists depends on the small crankshaft-like changes in orientation of the amide bond that allows maintenance of the overall helical parameters (helix pitch (p) and residues per turn (n)).The Pauling 3.6(13) α-helix fits the high-resolution experimental data with the minor exception of the amide-carbonyl electron density, but the previously associated backbone torsional angles (Φ, Ψ) needed slight modification to be reconciled with three-atom centered H-bonds and multipole electrostatics.Thus, a new standard helix, the 3.6(13/10)-, Némethy- or N-helix, is proposed.

View Article: PubMed Central - PubMed

Affiliation: Department of Biomedical Engineering, Washington University, St. Louis, MO, United States of America.

ABSTRACT
Theoretical and experimental evidence for non-linear hydrogen bonds in protein helices is ubiquitous. In particular, amide three-centered hydrogen bonds are common features of helices in high-resolution crystal structures of proteins. These high-resolution structures (1.0 to 1.5 Å nominal crystallographic resolution) position backbone atoms without significant bias from modeling constraints and identify Φ = -62°, ψ = -43 as the consensus backbone torsional angles of protein helices. These torsional angles preserve the atomic positions of α-β carbons of the classic Pauling α-helix while allowing the amide carbonyls to form bifurcated hydrogen bonds as first suggested by Némethy et al. in 1967. Molecular dynamics simulations of a capped 12-residue oligoalanine in water with AMOEBA (Atomic Multipole Optimized Energetics for Biomolecular Applications), a second-generation force field that includes multipole electrostatics and polarizability, reproduces the experimentally observed high-resolution helical conformation and correctly reorients the amide-bond carbonyls into bifurcated hydrogen bonds. This simple modification of backbone torsional angles reconciles experimental and theoretical views to provide a unified view of amide three-centered hydrogen bonds as crucial components of protein helices. The reason why they have been overlooked by structural biologists depends on the small crankshaft-like changes in orientation of the amide bond that allows maintenance of the overall helical parameters (helix pitch (p) and residues per turn (n)). The Pauling 3.6(13) α-helix fits the high-resolution experimental data with the minor exception of the amide-carbonyl electron density, but the previously associated backbone torsional angles (Φ, Ψ) needed slight modification to be reconciled with three-atom centered H-bonds and multipole electrostatics. Thus, a new standard helix, the 3.6(13/10)-, Némethy- or N-helix, is proposed. Due to the use of constraints from monopole force fields and assumed secondary structures used in low-resolution refinement of electron density of proteins, such structures in the PDB often show linear hydrogen bonding.

Show MeSH
Related in: MedlinePlus