Molecular Dynamics Analysis of the Conformations of a β-Hairpin Miniprotein

Hatfield, Marcus P. D.; Murphy, Richard F.; Lovas, Sándor

doi:10.1021/jp910465e

Cited by 24 publications

(44 citation statements)

References 47 publications

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“…The unfolding sequence can be well explained by the study of change in the interaction energy between different residues (Hatfield et al 2010;Das and Mukhopadhyay 2009). From Fig.…”

Section: Resultsmentioning

confidence: 94%

Molecular dynamics simulation exploration of unfolding and refolding of a ten-amino acid miniprotein

Zhao

Cheng

2011

Amino Acids

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Steered molecular dynamics simulations are performed to explore the unfolding and refolding processes of CLN025, a 10-residue beta-hairpin. In unfolding process, when CLN025 is pulled along the termini, the forceextension curve goes back and forth between negative and positive values not long after the beginning of simulation. That is so different from what happens in other peptides, where force is positive most of the time. The abnormal phenomenon indicates that electrostatic interaction between the charged termini plays an important role in the stability of the beta-hairpin. In the refolding process, the collapse to beta-hairpin-like conformations is very fast, within only 3.6 ns, which is driven by hydrophobic interactions at the termini, as the hydrophobic cluster involves aromatic rings of Tyr1, Tyr2, Trp9, and Tyr10. Our simulations improve the understanding on the structure and function of this type of miniprotein and will be helpful to further investigate the unfolding and refolding of more complex proteins.

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“…The unfolding sequence can be well explained by the study of change in the interaction energy between different residues (Hatfield et al 2010;Das and Mukhopadhyay 2009). From Fig.…”

Section: Resultsmentioning

confidence: 94%

Molecular dynamics simulation exploration of unfolding and refolding of a ten-amino acid miniprotein

Zhao

Cheng

2011

Amino Acids

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“…30,31 Here, the effect of various concentrations of urea and GdmCl on the conformation of CLN025 was examined by ECD and MD simulations. It was shown, that even high concentrations of these denaturants are unable to disrupt the β-hairpin conformation effectively.…”

Section: Discussionmentioning

confidence: 99%

“…30,31 In this study, MD simulations and Electronic Circular Dichroism (ECD) spectropolarimetry are used to investigate the conformational stability of the CLN025 β-hairpin in different concentrations of urea and GdmCl and to examine the changes in the H-bonds and weakly polar interactions. Conformational stability was investigated by ECD using 0 to 6 M GdmCl and 0 to 8 M urea in 0.5 M increments.…”

Section: Introductionmentioning

confidence: 99%

The CLN025 Decapeptide Retains a β-Hairpin Conformation in Urea and Guanidinium Chloride

2011

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The conformational stability of the β-hairpin miniprotein, CLN025, a variant of chignolin in which the N- and C-terminal Gly are replaced by Tyr, in various concentrations of GdmCl and urea was examined by Molecular Dynamics simulations and Electronic Circular Dichroism (ECD) spectropolarimetry. The peptide maintains its β-hairpin conformation in GdmCl and urea solutions. In GdmCl, Gly7 influences the turn to reduce the number of Asp3-Gly7 H-bonds and the Tyr1-Trp9 H-bond is lost. The structure of the peptide is less stable in 3 M GdmCl than in water or 6 M GdmCl, because the number of Asp3-Thr8 and Tyr1-Tyr10 H-bonds are reduced and the Tyr2 side-chain moves away from the Pro4 and Trp9 side-chains and towards the Tyr10 side-chain. This reduces the number of Tyr2-Pro4 CH-π interactions and Tyr2-Trp9 and Tyr1-Tyr10 aromatic-aromatic (Ar-Ar) interactions and increases the number of Tyr2-Tyr10 Ar-Ar interactions. In 6 M GdmCl at 300 and 333 K, the number of Tyr1-Tyr10 and Asp3-Thr8 H-bonds increases, but fewer structures have Tyr2-Pro4 CH-π and Tyr1-Tyr10 and Tyr2-Trp9 Ar-Ar interactions. In urea, Gly7 is in a mixture of β-turn and random meander structures and the number of Asp3-Thr6 and Tyr1-Tyr10 H-bonds are reduced as are the number of Tyr2-Pro4 CH-π interactions and Tyr1-Tyr10 and Tyr2-Trp9 Ar-Ar interactions. In 4 M urea, a shorter turn places Gly7 in to the β-sheet region and Tyr10 is pushed out into the solvent. In 8 M urea, the number of Asp3-Glu5 H-bonds is increased and the β-sheet is lost, but the electrostatic interaction between the charged termini is restored and a cation-π interaction between the indolyl ring of Trp9 and the positively charged N-terminus is formed. In 8 M urea at 333 K, the β-hairpin conformation is almost lost. The structure of CLN025 is stable, because the weakly polar interactions and H-bonds maintain the β-hairpin conformation in the various environments. CLN025 should not be considered a miniprotein, because it lacks a well-defined tertiary structure, it is resistant to denaturation, does not have an increased heat capacity near its melting temperature and the structures near and above the melting temperature retain a β-hairpin conformation.

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“…The MD simulations were performed using the GROMACS 4.5.4 package 28 by modifications of previous methods 29,30 and using the OPLS-AA/L force field 31 . Three initial structures of Ac-[Cys 13 ]Aβ(13–23)-NH 2 for the simulations were derived using experimental Aβ structures from the protein data bank (PDB) 32 : The structure with PDB id.…”

Section: Methodsmentioning

confidence: 99%

Molecular Mechanism of Misfolding and Aggregation of Aβ(13–23)

Lovas

Zhang

et al. 2013

J. Phys. Chem. B

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The misfolding and self-assembly of the amyloid-beta (Aβ) peptide into aggregates is a molecular signature of the development of Alzheimer’s disease but molecular mechanisms of the peptide aggregation remain unknown. Here, we combined Atomic Force Microscopy (AFM) and Molecular Dynamics (MD) simulations to characterize misfolding process of an Aβ peptide. Dynamic force spectroscopy AFM analysis showed that the peptide forms stable dimers with the lifetime of ~1 s. During MD simulations isolated monomers gradually adopt essentially similar non-structured conformations independent from the initial structure. However, when two monomers approach their structure changes dramatically and the conformational space for the two monomers become restricted. The arrangement of monomers in antiparallel orientation leads to the cooperative formation of β-sheet conformation. Interactions, including hydrogen bonds, salt bridges and weakly polar interactions of side chains stabilize the structure of the dimer. Under the applied force, the dimer, as during the AFM experiments, dissociates in a cooperative manner. Thus, misfolding of the Aβ peptide proceeds via the loss of conformational flexibility and formation of stable dimers suggesting their key role in the subsequent Aβ aggregation process.

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Molecular Dynamics Analysis of the Conformations of a β-Hairpin Miniprotein

Cited by 24 publications

References 47 publications

Molecular dynamics simulation exploration of unfolding and refolding of a ten-amino acid miniprotein

Molecular dynamics simulation exploration of unfolding and refolding of a ten-amino acid miniprotein

The CLN025 Decapeptide Retains a β-Hairpin Conformation in Urea and Guanidinium Chloride

Molecular Mechanism of Misfolding and Aggregation of Aβ(13–23)

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