Elucidating the folding problem of α-helices: local motifs, long-range electrostatics, ionic-strength dependence and prediction of NMR parameters 1 1Edited by A. R. Fersht

Lacroix, Emmanuel; Viguera, Ana Rosa; Serrano, Luís

doi:10.1006/jmbi.1998.2145

Cited by 418 publications

(405 citation statements)

References 64 publications

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“…To compare our results with AGADIR predictions, the helix content was calculated in accordance with the Chen equation 25 used by AGADIR. 22 The 1974 Chen equation for calculating percent helix values was later tested with Ala-based peptides of varying chain lengths and was refined slightly. 26 In the case of the E4K4 peptide, the helix content is high at 59%, close to the value predicted by the AGADIR algorithm (Table I).…”

Section: Resultsmentioning

confidence: 99%

“…21 Currently, one of the models, AGADIR, has been benchmarked against the largest selection of peptide sequences. 22 AGADIR is an algorithm that is based on helix-coil theory but modified to incorporate experimentally derived parameters. 18 The algorithm attempts to obtain an energetic description of the system by splitting the conformational energy of the peptide into a sum of energies: intrinsic helical tendencies of each residue, main chain-main chain hydrogen bonding, side chain-side chain interactions, helical dipole effects, and effects of nonhelical residues.…”

Section: Introductionmentioning

confidence: 99%

“…18 The algorithm attempts to obtain an energetic description of the system by splitting the conformational energy of the peptide into a sum of energies: intrinsic helical tendencies of each residue, main chain-main chain hydrogen bonding, side chain-side chain interactions, helical dipole effects, and effects of nonhelical residues. 22 While AGADIR predicts the helicity for peptides greater than one helical turn or four residues, there is a lack of experimental data for the helicity of short peptides (<9 amino acids). Ala-based peptides demonstrate only marginal helicity when 10 residues in length.…”

Section: Introductionmentioning

confidence: 99%

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Helicity of short E‐R/K peptides

et al. 2010

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Understanding the secondary structure of peptides is important in protein folding, enzyme function, and peptide-based drug design. Previous studies of synthetic Ala-based peptides (>12 a.a.) have demonstrated the role for charged side chain interactions involving Glu/Lys or Glu/Arg spaced three (i, i 1 3) or four (i, i 1 4) residues apart. The secondary structure of short peptides (<9 a.a.), however, has not been investigated. In this study, the effect of repetitive Glu/Lys or Glu/Arg side chain interactions, giving rise to E-R/K helices, on the helicity of short peptides was examined using circular dichroism. Short E-R/K-based peptides show significant helix content. Peptides containing one or more E-R interactions display greater helicity than those with similar E-K interactions. Significant helicity is achieved in Arg-based E-R/K peptides eight, six, and five amino acids long. In these short peptides, each additional i 1 3 and i 1 4 salt bridge has substantial contribution to fractional helix content. The E-R/K peptides exhibit a strongly linear melt curve indicative of noncooperative folding. The significant helicity of these short peptides with predictable dependence on number, position, and type of side chain interactions makes them an important consideration in peptide design.

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Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Helicity of short E‐R/K peptides

et al. 2010

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“…The effects of mutations on aggregation propensities were studied by TANGO [Fernandez-Escamilla et al, 2004;Linding et al, 2004] and calculations presented by Chiti et al [2003], for which a helical propensities were calculated with the program AGADIR [Muños and Serrano, 1994;Lacroix et al, 1998]. A script was written to implement the method of Chiti et al [2003].…”

Section: Methodsmentioning

confidence: 99%

Bioinformatic analysis of protein structure–function relationships: case study of leukocyte elastase (ELA2) missense mutations

Thusberg

Vihinen

2006

Hum. Mutat.

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For the Immunogenetics Special IssueCyclic and congenital neutropenia are caused by mutations in the human neutrophil elastase (HNE) gene (ELA2), leading to an immunodeficiency characterized by decreased or oscillating levels of neutrophils in the blood. The HNE mutations presumably cause loss of enzyme activity, consequently leading to compromised immune system function. To understand the structural basis for the disease, we implemented methods from bioinformatics to analyze all the known HNE missense mutations at both the sequence and structural level. Our results demonstrate that the 32 different mutations have diverse effects on HNE structure and function, affecting structural disorder and aggregation tendencies, stability maintaining contacts, and electrostatic properties. A large proportion of the mutations are located at conserved amino acids, which are usually essential in determining protein structure and function. The majority of the disease-causing HNE missense mutations lead to major structural changes and loss of stability in the protein. A few mutations also affect functional residues, leading into decreased catalytic activity or altered ligand binding. Our analysis reveals the putative effects of all known missense mutations in HNE, thus allowing the structural basis of cyclic and congenital neutropenia to be elucidated. We have employed and analyzed a set of some 30 different methods for predicting the effects of amino acid substitutions. We present results and experience from the analysis of the applicability of these methods in the analysis of numerous genes, proteins, and diseases to reveal protein structure-function relationships and disease genotype-phenotype correlations.

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“…The AGADIR program [93][94][95] calculates the residue-wise helical propensity of a polypeptide chain based on an empirical scale of propensity by amino acid type [96]. AGADIR predicts low overall intrinsic helical propensity for the FF domain (~2%).…”

Section: Mechanism Of Ff Foldingmentioning

confidence: 99%

Cross-Validation of the Structure of a Transiently Formed and Low Populated FF Domain Folding Intermediate Determined by Relaxation Dispersion NMR and CS-Rosetta

et al. 2011

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We have recently reported the atomic resolution structure of a low populated and transiently formed on-pathway folding intermediate of the FF domain from human HYPA/FBP11 [Korzhnev, D. M.; Religa, T. L.; Banachewicz, W.; Fersht, A. R.; Kay, L.E. Science 2011, 329, 1312–1316]. The structure was determined on the basis of backbone chemical shift and bond vector orientation restraints of the invisible intermediate state measured using relaxation dispersion nuclear magnetic resonance (NMR) spectroscopy that were subsequently input into the database structure determination program, CS-Rosetta. As a cross-validation of the structure so produced, we present here the solution structure of a mimic of the folding intermediate that is highly populated in solution, obtained from the wild-type domain by mutagenesis that destabilizes the native state. The relaxation dispersion/CS-Rosetta structures of the intermediate are within 2 Å of those of the mimic, with the nonnative interactions in the intermediate also observed in the mimic. This strongly confirms the structure of the FF domain folding intermediate, in particular, and validates the use of relaxation dispersion derived restraints in structural studies of invisible excited states, in general.

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Elucidating the folding problem of α-helices: local motifs, long-range electrostatics, ionic-strength dependence and prediction of NMR parameters 1 1Edited by A. R. Fersht

Cited by 418 publications

References 64 publications

Helicity of short E‐R/K peptides

Helicity of short E‐R/K peptides

Bioinformatic analysis of protein structure–function relationships: case study of leukocyte elastase (ELA2) missense mutations

Cross-Validation of the Structure of a Transiently Formed and Low Populated FF Domain Folding Intermediate Determined by Relaxation Dispersion NMR and CS-Rosetta

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