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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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Schematic stick-figure diagrams of α-helix (top left and middle) and 310-helix (bottom left and right) helices.
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pone.0123146.g002: Schematic stick-figure diagrams of α-helix (top left and middle) and 310-helix (bottom left and right) helices.

Mentions: In 1953, Donohue applied similar constraints with slightly different parameters to arrive at an alternative helical configuration (Fig 2), one with a rise of 3 residues-per-turn and 10 atoms (310-helix) in the hydrogen-bonded ring [7]. Where the α-helix places residues i and i+4 with a hydrogen bond, the 310-helix is a longer and more tightly wound configuration with hydrogen bonds between residues i and i+3 (Fig 2). Némethy et al. analyzed the equations derived by Miyazawa [8] regarding helical parameters (helix pitch (p) and residues per turn (n)) and proposed the αII-helix in 1967 that exactly fit the helical parameters of the Pauling α-helix, but lacked amide hydrogen bonds [9]. As the importance of amide H-bonds and three-centered hydrogen bonding (Fig 1) was just beginning to be appreciated [10], the αII-helix disappeared from the literature. In the Némethy et al paper [9], however, an intermediate helix between the α-helix and the αII-helix was illustrated (Fig 3) with bifurcated hydrogen bonds and the same helical pitch and residues-per-turn as the Pauling α-helix. These are exactly the properties observed for helices in high-resolution crystal structures from the Protein Data Bank (PDB) [11] that we refer to as Némethy-, N- or 3.613/10-helices in this paper. The crucial insight by Némethy et al. was recognition that helical parameters are not tightly coupled to backbone torsional angles.


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)

Schematic stick-figure diagrams of α-helix (top left and middle) and 310-helix (bottom left and right) helices.
© Copyright Policy
Related In: Results  -  Collection

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

pone.0123146.g002: Schematic stick-figure diagrams of α-helix (top left and middle) and 310-helix (bottom left and right) helices.
Mentions: In 1953, Donohue applied similar constraints with slightly different parameters to arrive at an alternative helical configuration (Fig 2), one with a rise of 3 residues-per-turn and 10 atoms (310-helix) in the hydrogen-bonded ring [7]. Where the α-helix places residues i and i+4 with a hydrogen bond, the 310-helix is a longer and more tightly wound configuration with hydrogen bonds between residues i and i+3 (Fig 2). Némethy et al. analyzed the equations derived by Miyazawa [8] regarding helical parameters (helix pitch (p) and residues per turn (n)) and proposed the αII-helix in 1967 that exactly fit the helical parameters of the Pauling α-helix, but lacked amide hydrogen bonds [9]. As the importance of amide H-bonds and three-centered hydrogen bonding (Fig 1) was just beginning to be appreciated [10], the αII-helix disappeared from the literature. In the Némethy et al paper [9], however, an intermediate helix between the α-helix and the αII-helix was illustrated (Fig 3) with bifurcated hydrogen bonds and the same helical pitch and residues-per-turn as the Pauling α-helix. These are exactly the properties observed for helices in high-resolution crystal structures from the Protein Data Bank (PDB) [11] that we refer to as Némethy-, N- or 3.613/10-helices in this paper. The crucial insight by Némethy et al. was recognition that helical parameters are not tightly coupled to backbone torsional angles.

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