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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

Predicted fraction of time each residue is in a helix (α-helix, 310 Helix or π Helix) or strand (β-sheet or β-Bridge).The predicted fractions for rat are shown on the left for the Amberff99sb*-ILDN with TIP3P, CHARMM22* with TIP4P, CHARMM22/CMAP with TIPS3P, and Gromos96 53a6 with SPC force fields. On the right, the predicted fractions of human amylin are shown for Amberff99sb*-ILDN with TIP3P, Amberff03w with TIP4P, CHARMM22* with TIP4P, and Gromos96 53a6 with SPC.
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pone.0134091.g005: Predicted fraction of time each residue is in a helix (α-helix, 310 Helix or π Helix) or strand (β-sheet or β-Bridge).The predicted fractions for rat are shown on the left for the Amberff99sb*-ILDN with TIP3P, CHARMM22* with TIP4P, CHARMM22/CMAP with TIPS3P, and Gromos96 53a6 with SPC force fields. On the right, the predicted fractions of human amylin are shown for Amberff99sb*-ILDN with TIP3P, Amberff03w with TIP4P, CHARMM22* with TIP4P, and Gromos96 53a6 with SPC.

Mentions: These overall helix and strand propensities are broken down by residue in Fig 5. CHARMM22/CMAP exhibits the most helical behavior. This is concentrated between residues 5–23 as observed in experiments and secondary structure prediction algorithms. For this force field, these residues are usually in an α-helix. This α-helix is broken by glycine at residue 24. Another helix occasionally forms in the tail between residues 27 and 36. This is predicted to be present roughly 30% of the time by CHARMM22/CMAP. Amberff99sb*-ILDN is the next most helical force field. It follows the same broad trends with intermittent helices between residues 5–23 and 27–36. These are followed by Amberff03w with TIP4P2005 and CHARMM22* with TIPS3P. CHARMM22* predicts a helix more frequently between residues 27–36 than between 7–23.


Secondary Structure of Rat and Human Amylin across Force Fields.

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

Predicted fraction of time each residue is in a helix (α-helix, 310 Helix or π Helix) or strand (β-sheet or β-Bridge).The predicted fractions for rat are shown on the left for the Amberff99sb*-ILDN with TIP3P, CHARMM22* with TIP4P, CHARMM22/CMAP with TIPS3P, and Gromos96 53a6 with SPC force fields. On the right, the predicted fractions of human amylin are shown for Amberff99sb*-ILDN with TIP3P, Amberff03w with TIP4P, CHARMM22* with TIP4P, and Gromos96 53a6 with SPC.
© Copyright Policy
Related In: Results  -  Collection

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

pone.0134091.g005: Predicted fraction of time each residue is in a helix (α-helix, 310 Helix or π Helix) or strand (β-sheet or β-Bridge).The predicted fractions for rat are shown on the left for the Amberff99sb*-ILDN with TIP3P, CHARMM22* with TIP4P, CHARMM22/CMAP with TIPS3P, and Gromos96 53a6 with SPC force fields. On the right, the predicted fractions of human amylin are shown for Amberff99sb*-ILDN with TIP3P, Amberff03w with TIP4P, CHARMM22* with TIP4P, and Gromos96 53a6 with SPC.
Mentions: These overall helix and strand propensities are broken down by residue in Fig 5. CHARMM22/CMAP exhibits the most helical behavior. This is concentrated between residues 5–23 as observed in experiments and secondary structure prediction algorithms. For this force field, these residues are usually in an α-helix. This α-helix is broken by glycine at residue 24. Another helix occasionally forms in the tail between residues 27 and 36. This is predicted to be present roughly 30% of the time by CHARMM22/CMAP. Amberff99sb*-ILDN is the next most helical force field. It follows the same broad trends with intermittent helices between residues 5–23 and 27–36. These are followed by Amberff03w with TIP4P2005 and CHARMM22* with TIPS3P. CHARMM22* predicts a helix more frequently between residues 27–36 than between 7–23.

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