Modulation of intrinsic φ,ψ propensities of amino acids by neighbouring residues in the coil regions of protein structures: NMR analysis and dissection of a β-hairpin peptide 1 1Edited by P. E. Wright

Griffiths-Jones, Sam; Sharman, Gary J.; Maynard, Allister J.; Searle, Mark S.

doi:10.1006/jmbi.1998.2264

Cited by 57 publications

(82 citation statements)

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“…These analyses were aimed at obtaining intrinsic conformational preferences of amino acids in contrast to preferences dictated by the role of the amino acids in protein structure, packing and solubility. The exposed portions of the protein lacking regular secondary structure, experience a striking increase in the number of points in the ␣ L region (30), as observed in our peptide simulations. In agreement with our Val results, Griffiths-Jones et al (30) found that context is critical for ␤-structure, which is determined primarily by side chain interactions, as found in earlier experiments (31).…”

Section: Comparison Of Amino Acid Conformational Preferences In Peptisupporting

confidence: 56%

“…The ''unstructured'' or ''coil'' regions of proteins have been analyzed independently of the more well ordered secondary structure (26)(27)(28)(29)(30). These analyses were aimed at obtaining intrinsic conformational preferences of amino acids in contrast to preferences dictated by the role of the amino acids in protein structure, packing and solubility.…”

Section: Comparison Of Amino Acid Conformational Preferences In Peptimentioning

confidence: 99%

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The intrinsic conformational propensities of the 20 naturally occurring amino acids and reflection of these propensities in proteins

Beck

Alonso

Inoyama

et al. 2008

Proc. Natl. Acad. Sci. U.S.A.

125

183

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Here, we compare the distributions of main chain (⌽,⌿) angles (i.e., Ramachandran maps) of the 20 naturally occurring amino acids in three contexts: (i) molecular dynamics (MD) simulations of GlyGly-X-Gly-Gly pentapeptides in water at 298 K with exhaustive sampling, where X ‫؍‬ the amino acid in question; (ii) 188 independent protein simulations in water at 298 K from our Dynameomics Project; and (iii) static crystal and NMR structures from the Protein Data Bank. The GGXGG peptide series is often used as a model of the unstructured denatured state of proteins. The sampling in the peptide MD simulations is neither random nor uniform. Instead, individual amino acids show preferences for particular conformations, but the peptide is dynamic, and interconversion between conformers is facile. For a given amino acid, the (⌽,⌿) distributions in the protein simulations and the Protein Data Bank are very similar and often distinct from those in the peptide simulations. Comparison between the peptide and protein simulations shows that packing constraints, solvation, and the tendency for particular amino acids to be used for specific structural motifs can overwhelm the ''intrinsic propensities'' of amino acids for particular (⌽,⌿) conformations. We also compare our helical propensities with experimental consensus values using the host-guest method, which appear to be determined largely by context and not necessarily the intrinsic conformational propensities of the guest residues. These simulations represent an improved coil library free from contextual effects to better model intrinsic conformational propensities and provide a detailed view of conformations making up the ''random coil'' state.coil library ͉ Dynameomics ͉ molecular dynamics ͉ protein folding ͉ host-guest P rotein secondary structure was predicted before the atomic structures of protein were determined (1-3). Conformational preferences of the amino acids were also estimated very early on, beginning with Ramachandran's ''map'' in 1963, ''based solely on repulsive van der Waals'' forces in dipeptides (4, 5). Remarkably, these predictions regarding structure and conformational preferences were later largely validated in protein crystal structures (6-8).In the protein folding field, these preferences are seen as both means of excluding regions of conformational space and as driving forces for the formation of secondary structure, both of which limit and bias the necessary search of conformational space required during protein folding.(⌽,⌿) dihedral angle distributions are increasingly used to check the validity of structures. Although there can be no doubt about the general tendency of amino acids in globular proteins to populate some regions of (⌽,⌿) space relative to others, the use of such distributions to judge and refine structures leads to dangerous circular reasoning. That is, (⌽,⌿) preferences are used as tests of crystal structures, and those very crystal structures are then used to define and support the Ramachandran (⌽,⌿) angle distributions.Many exper...

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Section: Comparison Of Amino Acid Conformational Preferences In Peptisupporting

confidence: 56%

Section: Comparison Of Amino Acid Conformational Preferences In Peptimentioning

confidence: 99%

The intrinsic conformational propensities of the 20 naturally occurring amino acids and reflection of these propensities in proteins

Beck

Alonso

Inoyama

et al. 2008

Proc. Natl. Acad. Sci. U.S.A.

125

183

View full text Add to dashboard Cite

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“…There has also been much speculation and some experimental evidence to support the idea that hairpins may play a key role in initiating the assembly of b-structures in folding~Ptitsyn, 1991; Muñoz et al, 1997!. In recent years, there has been considerable interest in using b-hairpins as model systems for developing our understanding of b-structure and several examples both of protein fragments and of de novo designed peptides capable of folding autonomously as hairpins have now been identified~Blanco et al, 1994;Searle et al, 1995;Ramirez-Alvarado et al, 1996!. The lessons learned from exploring the effects of sequence variations in these systems have been reviewed recently~Griffiths- Jones et al, 1998;Ramirez-Alvarado et al, 1999!. Sequence variations cannot only alter the stability of hairpin structures, but also the register of the b-strands. In the arms of the hairpin, a high b-propensity of individual residues is important for stability.…”

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confidence: 99%

Structural characterization of a mutant peptide derived from ubiquitin: Implications for protein folding

Zerella

Chen

Evans³

et al. 2000

Protein Science

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The formation of the N-terminal b-hairpin of ubiquitin is thought to be an early event in the folding of this small protein.Previously, we have shown that a peptide corresponding to residues 1-17 of ubiquitin folds autonomously and is likely to have a native-like hairpin register. To investigate the causes of the stability of this fold, we have made mutations in the amino acids at the apex of the turn. We find that in a peptide where Thr9 is replaced by Asp, U~1-17!T9D, the native conformation is stabilized with respect to the wild-type sequence, so much so that we are able to characterize the structure of the mutant peptide fully by NMR spectroscopy. The data indicate that U~1-17!T9D peptide does indeed form a hairpin with a native-like register and a type I turn with a G1 b-bulge, as in the full-length protein. The reason for the greater stability of the U~1-17!T9D mutant remains uncertain, but there are nuclear Overhauser effects between the side chains of Asp9 and Lys11, which may indicate that a charge-charge interaction between these residues is responsible.Keywords: b-hairpin; b-sheet; NMR; peptide; peptide conformations; structure; ubiquitin; X-PLOR The b-hairpin is one of the most commonly occurring structural motifs in globular protein folds: most antiparallel b-sheets contain at least some strand pairs that are contiguous in sequence and connected by a relatively tight turn. There has also been much speculation and some experimental evidence to support the idea that hairpins may play a key role in initiating the assembly of b-structures in folding~Ptitsyn, 1991; Muñoz et al., 1997!. In recent years, there has been considerable interest in using b-hairpins as model systems for developing our understanding of b-structure and several examples both of protein fragments and of de novo designed peptides capable of folding autonomously as hairpins have now been identified~Blanco et al., 1994;Searle et al., 1995;Ramirez-Alvarado et al., 1996!. The lessons learned from exploring the effects of sequence variations in these systems have been reviewed recently~Griffiths- Jones et al., 1998;Ramirez-Alvarado et al., 1999!. Sequence variations cannot only alter the stability of hairpin structures, but also the register of the b-strands. In the arms of the hairpin, a high b-propensity of individual residues is important for stability. However, specific pairwise contacts, especially between side chains interacting across the hairpin, are also important and optimization of these is hypothesized to be an important contribution in fixing the strand register~Smith & Regan, 1995;Wouters & Curmi, 1995;Hutchinson et al., 1998!. The turn sequence is also important: it is clear from analysis of hairpins within intact protein structures that some turn types are prevalent in b-hairpins. Sequence compatibility with these preferred structures has been shown in peptide studies to be an important determinant of structural specificity and stability~Ramirez- Alvarado et al., 1997;De Alba et al., 1999;Griffiths-Jones et al., 19...

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“…However, Searle and coworkers noticed that despite apparently large differences in the propensity among Thr, Ile, and Val, the average 3 J values calculated ($7.5 6 0.2 Hz) from the distributions, remained very similar in proteins. 28 Table III compares the selected main-chain torsion angles of the correlated model peptides across theXaa-Thr-sequence. A comparative analysis tends to reveal the influence of discrete stereochemistry of the Xaa residue on the overall preferred molecular conformations.…”

Section: 82mentioning

confidence: 99%

“…An evaluation of modulation of intrinsic , propensities of various amino acids revealed that despite a high secondary structure propensity to form -sheet structures, the Thr residue showed a surprisingly low value for P , i.e., Thr exhibited a relatively low P value (57%) as compared to the C -branched Ile (77%) and Val (79%). 28 Nevertheless, in an attempt to resolve the relative -sheet-forming propensities of the proteinogenic residues, as analyzed by protein engineering experiments, Minor and Kim 13 demonstrated that a Thr has the highest intrinsic propensity for a -sheet conformation. The Zimm-Bragg parameters reported for encoding residues, 36 in conjunction with the results of empirical conformational energy calculations performed on Ac-Thr-NHCH 3 , 37,38 indicated that a Thr residue exhibits a strong tendency to hydrogen bond to main-chain atoms particularly, in a nonhelical conformation.…”

Section: Introductionmentioning

confidence: 98%

Characterization of β‐turn and Asx‐turns mimicry in a model peptide: Stabilization via CH · · · O interaction

Thakur

Kishore

2006

Biopolymers

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The chemical synthesis and single-crystal X-ray diffraction analysis of a model peptide, Boc-Thr-Thr-NH2 (1) comprised of proteinogenic residues bearing an amphiphilic Cbeta -stereogenic center, has been described. Interestingly, the analysis of its molecular structure revealed the existence of a distinct conformation that mimics a typical beta-turn and Asx-turns, i.e., the two Thr residues occupy the left- and right-corner positions. The main-chain torsion angles of the N- and C-terminal residues i.e., semiextended: phi = -68.9 degrees , psi = 128.6 degrees ; semifolded: phi = -138.1 degrees , psi = 2.5 degrees conformations, respectively, in conjunction with a gauche- disposition of the obligatory C-terminus Thr CgammaH3 group, characterize the occurrence of the newly described beta-turn- and Asx-turns-like topology. The preferred molecular structure is suggested to be stabilized by an effective nonconventional main-chain to side-chain Ci=O . . . H--Cgamma(i+2)-type intraturn hydrogen bond. Noteworthy, the observed topology of the resulting 10-membered hydrogen-bonded ring is essentially similar to the one perceived for a classical beta-turn and the Asx-turns, stabilized by a conventional intraturn hydrogen bond. Considering the signs as well as magnitudes of the backbone torsion angles and the orientation of the central peptide bond, the overall mimicked topology resembles the type II beta-turn or type II Asx-turns. An analysis of Xaa-Thr sequences in high-resolution X-ray elucidated protein structures revealed the novel topology prevalence in functional proteins (unpublished). In view of indubitable structural as well as functional importance of nonconventional interactions in bioorganic and biomacromolecules, we intend to highlight the participation of Thr CgammaH in the creation of a short-range C=O . . . H--Cgamma -type interaction in peptides and proteins.

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Modulation of intrinsic φ,ψ propensities of amino acids by neighbouring residues in the coil regions of protein structures: NMR analysis and dissection of a β-hairpin peptide 1 1Edited by P. E. Wright

Cited by 57 publications

References 50 publications

The intrinsic conformational propensities of the 20 naturally occurring amino acids and reflection of these propensities in proteins

The intrinsic conformational propensities of the 20 naturally occurring amino acids and reflection of these propensities in proteins

Structural characterization of a mutant peptide derived from ubiquitin: Implications for protein folding

Characterization of β‐turn and Asx‐turns mimicry in a model peptide: Stabilization via CH · · · O interaction

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