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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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The Φ, Ψ angles distribution of the data filtered with H-bond distance (<4 Å) and Φ, Ψ angles range (-100 -> 0, -70 -> 0).The median of Φ, Ψ angles was Φ-72.8, Ψ-33.4.
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pone.0123146.g014: The Φ, Ψ angles distribution of the data filtered with H-bond distance (<4 Å) and Φ, Ψ angles range (-100 -> 0, -70 -> 0).The median of Φ, Ψ angles was Φ-72.8, Ψ-33.4.

Mentions: As the structure was started in a helical conformation, this was confirmed by monitoring the changes in conformation as a function of length of simulation (Fig 12). A Ramachandran plot from the MD simulation demonstrated significant sampling of torsional space different from the starting helical conformation to provide evidence for sufficient sampling (Fig 13). Only a single peak was observed in the region of φ = [-100 → 0], ψ = [-70 → 0] region. To further determine the center of the structures, structural filtering based on α- and 310-helical hydrogen bond lengths (i.e., < 4 Å) and φ,ψ angles was performed (Fig 14). Both φ,ψ angles and i→i+4 distances followed normal distribution with slight skewing to the left of i→i+4 hydrogen bonds. Considering the strong penalty for steric overlap, an approximately normal distribution resulted. The “average” structure had helical backbone torsions φ = −72.78, ψ = −33.43 and i→i+3 = 2.97 Å; i→i+4 = 2.28 Å hydrogen-bond distances (Fig 15) with a conformation that resembled the α- and experimental Némethy-, N- or 3.613/10-helix (Fig 16).


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 Φ, Ψ angles distribution of the data filtered with H-bond distance (<4 Å) and Φ, Ψ angles range (-100 -> 0, -70 -> 0).The median of Φ, Ψ angles was Φ-72.8, Ψ-33.4.
© Copyright Policy
Related In: Results  -  Collection

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

pone.0123146.g014: The Φ, Ψ angles distribution of the data filtered with H-bond distance (<4 Å) and Φ, Ψ angles range (-100 -> 0, -70 -> 0).The median of Φ, Ψ angles was Φ-72.8, Ψ-33.4.
Mentions: As the structure was started in a helical conformation, this was confirmed by monitoring the changes in conformation as a function of length of simulation (Fig 12). A Ramachandran plot from the MD simulation demonstrated significant sampling of torsional space different from the starting helical conformation to provide evidence for sufficient sampling (Fig 13). Only a single peak was observed in the region of φ = [-100 → 0], ψ = [-70 → 0] region. To further determine the center of the structures, structural filtering based on α- and 310-helical hydrogen bond lengths (i.e., < 4 Å) and φ,ψ angles was performed (Fig 14). Both φ,ψ angles and i→i+4 distances followed normal distribution with slight skewing to the left of i→i+4 hydrogen bonds. Considering the strong penalty for steric overlap, an approximately normal distribution resulted. The “average” structure had helical backbone torsions φ = −72.78, ψ = −33.43 and i→i+3 = 2.97 Å; i→i+4 = 2.28 Å hydrogen-bond distances (Fig 15) with a conformation that resembled the α- and experimental Némethy-, N- or 3.613/10-helix (Fig 16).

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