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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 hydrogen-bonding matrix of 12-residue capped oligo-Ala (left) and oligo-Aib (right) from AMOEBA replica-exchange MD simulation.The acceptor+1(i->i+2) and acceptor+2(i->i+3), indicating 310 helix) in oligo-Aib is more heavily occupied than in oligo-Ala.
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pone.0123146.g020: The hydrogen-bonding matrix of 12-residue capped oligo-Ala (left) and oligo-Aib (right) from AMOEBA replica-exchange MD simulation.The acceptor+1(i->i+2) and acceptor+2(i->i+3), indicating 310 helix) in oligo-Aib is more heavily occupied than in oligo-Ala.

Mentions: While the analysis of Hodgkin et al. was very thorough, it depended on an early version of AMBER. In order to test this hypothesis with a more precise force field, MD simulations in water of 12-residue capped oligoalanine and oligo-α-aminoisobutyric acid were preformed with AMOEBA. The Ramachandran plots from the 10-nsec replica-exchange MD simulations are compared (Fig 19). The hydrogen-bonding matrices for oligo-Ala and oligo-Aib from the MD simulations (Fig 20) show a significant increase in 310-like helices in the oligo-Aib peptide. Thus, introduction of Aib residues enhances the preference for 310-like helices and limits the relevance of data from such peptides to protein helices.


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 hydrogen-bonding matrix of 12-residue capped oligo-Ala (left) and oligo-Aib (right) from AMOEBA replica-exchange MD simulation.The acceptor+1(i->i+2) and acceptor+2(i->i+3), indicating 310 helix) in oligo-Aib is more heavily occupied than in oligo-Ala.
© Copyright Policy
Related In: Results  -  Collection

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

pone.0123146.g020: The hydrogen-bonding matrix of 12-residue capped oligo-Ala (left) and oligo-Aib (right) from AMOEBA replica-exchange MD simulation.The acceptor+1(i->i+2) and acceptor+2(i->i+3), indicating 310 helix) in oligo-Aib is more heavily occupied than in oligo-Ala.
Mentions: While the analysis of Hodgkin et al. was very thorough, it depended on an early version of AMBER. In order to test this hypothesis with a more precise force field, MD simulations in water of 12-residue capped oligoalanine and oligo-α-aminoisobutyric acid were preformed with AMOEBA. The Ramachandran plots from the 10-nsec replica-exchange MD simulations are compared (Fig 19). The hydrogen-bonding matrices for oligo-Ala and oligo-Aib from the MD simulations (Fig 20) show a significant increase in 310-like helices in the oligo-Aib peptide. Thus, introduction of Aib residues enhances the preference for 310-like helices and limits the relevance of data from such peptides to protein helices.

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