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Secondary Structure of Rat and Human Amylin across Force Fields.

Hoffmann KQ, McGovern M, Chiu CC, de Pablo JJ - PLoS ONE (2015)

Bottom Line: Rat amylin differs from human amylin by only 6 residues; however, it does not form fibrils.In contrast to previous reports, our findings suggest that the equilibrium conformations of human and rat amylin are remarkably similar, but that subtle differences arise in transient alpha-helical and beta-strand containing structures that the human peptide can more readily adopt.We hypothesize that these transient states enable dynamic pathways that facilitate the formation of aggregates and, eventually, amyloid fibrils.

View Article: PubMed Central - PubMed

Affiliation: Institute for Molecular Engineering, University of Chicago, Chicago, Illinois, United States of America.

ABSTRACT
The aggregation of human amylin has been strongly implicated in the progression of Type II diabetes. This 37-residue peptide forms a variety of secondary structures, including random coils, α-helices, and β-hairpins. The balance between these structures depends on the chemical environment, making amylin an ideal candidate to examine inherent biases in force fields. Rat amylin differs from human amylin by only 6 residues; however, it does not form fibrils. Therefore it provides a useful complement to human amylin in studies of the key events along the aggregation pathway. In this work, the free energy of rat and human amylin was determined as a function of α-helix and β-hairpin content for the Gromos96 53a6, OPLS-AA/L, CHARMM22/CMAP, CHARMM22*, Amberff99sb*-ILDN, and Amberff03w force fields using advanced sampling techniques, specifically bias exchange metadynamics. This work represents a first systematic attempt to evaluate the conformations and the corresponding free energy of a large, clinically relevant disordered peptide in solution across force fields. The NMR chemical shifts of rIAPP were calculated for each of the force fields using their respective free energy maps, allowing us to quantitatively assess their predictions. We show that the predicted distribution of secondary structures is sensitive to the choice of force-field: Gromos53a6 is biased towards β-hairpins, while CHARMM22/CMAP predicts structures that are overly α-helical. OPLS-AA/L favors disordered structures. Amberff99sb*-ILDN, AmberFF03w and CHARMM22* provide the balance between secondary structures that is most consistent with available experimental data. In contrast to previous reports, our findings suggest that the equilibrium conformations of human and rat amylin are remarkably similar, but that subtle differences arise in transient alpha-helical and beta-strand containing structures that the human peptide can more readily adopt. We hypothesize that these transient states enable dynamic pathways that facilitate the formation of aggregates and, eventually, amyloid fibrils.

No MeSH data available.


Related in: MedlinePlus

Free energy of human amylin as a function of αRMSD and βRMSD for various force fields.The darker regions indicate regions of lower free energy.
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pone.0134091.g002: Free energy of human amylin as a function of αRMSD and βRMSD for various force fields.The darker regions indicate regions of lower free energy.

Mentions: The free energy surfaces of human amylin are shown in Fig 2. The Gromos96 53a6 force field predicts much more β-sheet character than the other force fields—much greater than that predicted for rat amylin. The other force fields follow trends similar to those seen above for rIAPP: the Amber and CHARMM22* force fields predict mostly random coil structures with a small amount of α-helical and β-hairpin structures. OPLS-AA/L is also mostly random coil and predicts more β-sheet structures compared with rIAPP. The free energy of the β-sheet structures is also lower than that observed in all other force fields except Gromos96 53a6.


Secondary Structure of Rat and Human Amylin across Force Fields.

Hoffmann KQ, McGovern M, Chiu CC, de Pablo JJ - PLoS ONE (2015)

Free energy of human amylin as a function of αRMSD and βRMSD for various force fields.The darker regions indicate regions of lower free energy.
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4519342&req=5

pone.0134091.g002: Free energy of human amylin as a function of αRMSD and βRMSD for various force fields.The darker regions indicate regions of lower free energy.
Mentions: The free energy surfaces of human amylin are shown in Fig 2. The Gromos96 53a6 force field predicts much more β-sheet character than the other force fields—much greater than that predicted for rat amylin. The other force fields follow trends similar to those seen above for rIAPP: the Amber and CHARMM22* force fields predict mostly random coil structures with a small amount of α-helical and β-hairpin structures. OPLS-AA/L is also mostly random coil and predicts more β-sheet structures compared with rIAPP. The free energy of the β-sheet structures is also lower than that observed in all other force fields except Gromos96 53a6.

Bottom Line: Rat amylin differs from human amylin by only 6 residues; however, it does not form fibrils.In contrast to previous reports, our findings suggest that the equilibrium conformations of human and rat amylin are remarkably similar, but that subtle differences arise in transient alpha-helical and beta-strand containing structures that the human peptide can more readily adopt.We hypothesize that these transient states enable dynamic pathways that facilitate the formation of aggregates and, eventually, amyloid fibrils.

View Article: PubMed Central - PubMed

Affiliation: Institute for Molecular Engineering, University of Chicago, Chicago, Illinois, United States of America.

ABSTRACT
The aggregation of human amylin has been strongly implicated in the progression of Type II diabetes. This 37-residue peptide forms a variety of secondary structures, including random coils, α-helices, and β-hairpins. The balance between these structures depends on the chemical environment, making amylin an ideal candidate to examine inherent biases in force fields. Rat amylin differs from human amylin by only 6 residues; however, it does not form fibrils. Therefore it provides a useful complement to human amylin in studies of the key events along the aggregation pathway. In this work, the free energy of rat and human amylin was determined as a function of α-helix and β-hairpin content for the Gromos96 53a6, OPLS-AA/L, CHARMM22/CMAP, CHARMM22*, Amberff99sb*-ILDN, and Amberff03w force fields using advanced sampling techniques, specifically bias exchange metadynamics. This work represents a first systematic attempt to evaluate the conformations and the corresponding free energy of a large, clinically relevant disordered peptide in solution across force fields. The NMR chemical shifts of rIAPP were calculated for each of the force fields using their respective free energy maps, allowing us to quantitatively assess their predictions. We show that the predicted distribution of secondary structures is sensitive to the choice of force-field: Gromos53a6 is biased towards β-hairpins, while CHARMM22/CMAP predicts structures that are overly α-helical. OPLS-AA/L favors disordered structures. Amberff99sb*-ILDN, AmberFF03w and CHARMM22* provide the balance between secondary structures that is most consistent with available experimental data. In contrast to previous reports, our findings suggest that the equilibrium conformations of human and rat amylin are remarkably similar, but that subtle differences arise in transient alpha-helical and beta-strand containing structures that the human peptide can more readily adopt. We hypothesize that these transient states enable dynamic pathways that facilitate the formation of aggregates and, eventually, amyloid fibrils.

No MeSH data available.


Related in: MedlinePlus