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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

Helmholtz free energy in kT versus βRMSD for rat and human amylin.The βRMSD is correlated with the number of residues in a β-hairpin. The results for rIAPP are shown using solid lines, while the results for hIAPP are given in dashed lines. The Helmholtz free energy is shown for Amberff99sb*-ILDN with TIP3P (black), Amberff03w with TIP4P2005 (red), and CHARMM22* with TIP4P (blue).
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pone.0134091.g008: Helmholtz free energy in kT versus βRMSD for rat and human amylin.The βRMSD is correlated with the number of residues in a β-hairpin. The results for rIAPP are shown using solid lines, while the results for hIAPP are given in dashed lines. The Helmholtz free energy is shown for Amberff99sb*-ILDN with TIP3P (black), Amberff03w with TIP4P2005 (red), and CHARMM22* with TIP4P (blue).

Mentions: The absence of this decrease in strand propensity is reflected in the formation of larger β-hairpins in hIAPP compared to rIAPP. Fig 8 shows the free energy versus βRMSD of rIAPP and hIAPP for Amberff99sb*-ILDN with TIP3P, Amberff03w with TIP4P2005, and CHARMM22* with TIP4P. When the free energy along the αRMSD coordinate is integrated out, a noticeable trend appears. In all three cases, when the βRMSD is large, as in the case of a large hairpin, the free energy of hIAPP is less than that of rIAPP. We hypothesize that the ability of human amylin to form α-helices and β-hairpins across residues 24–29 allows the formation of a much more diverse set of potential transition structures, which could be responsible for the propensity of hIAPP to form fibrils. Indeed, for both the 2-fold [113] and 3-fold [93] models for amylin, large β-sheets are present. Furthermore, residues 28 and 29, which had no observed strand content in rIAPP but occasionally formed β-sheets for hIAPP, are predicted to be part of the β-strands experimentally observed in hIAPP. These residues are in the β-sheet region of conformations identified as intermediates in the formation of amyloid fibrils [114]. The formation of a β-hairpin involving these atoms has also been identified as part of a transition from the α-helical to β-hairpin conformations of hIAPP [115].


Secondary Structure of Rat and Human Amylin across Force Fields.

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

Helmholtz free energy in kT versus βRMSD for rat and human amylin.The βRMSD is correlated with the number of residues in a β-hairpin. The results for rIAPP are shown using solid lines, while the results for hIAPP are given in dashed lines. The Helmholtz free energy is shown for Amberff99sb*-ILDN with TIP3P (black), Amberff03w with TIP4P2005 (red), and CHARMM22* with TIP4P (blue).
© Copyright Policy
Related In: Results  -  Collection

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

pone.0134091.g008: Helmholtz free energy in kT versus βRMSD for rat and human amylin.The βRMSD is correlated with the number of residues in a β-hairpin. The results for rIAPP are shown using solid lines, while the results for hIAPP are given in dashed lines. The Helmholtz free energy is shown for Amberff99sb*-ILDN with TIP3P (black), Amberff03w with TIP4P2005 (red), and CHARMM22* with TIP4P (blue).
Mentions: The absence of this decrease in strand propensity is reflected in the formation of larger β-hairpins in hIAPP compared to rIAPP. Fig 8 shows the free energy versus βRMSD of rIAPP and hIAPP for Amberff99sb*-ILDN with TIP3P, Amberff03w with TIP4P2005, and CHARMM22* with TIP4P. When the free energy along the αRMSD coordinate is integrated out, a noticeable trend appears. In all three cases, when the βRMSD is large, as in the case of a large hairpin, the free energy of hIAPP is less than that of rIAPP. We hypothesize that the ability of human amylin to form α-helices and β-hairpins across residues 24–29 allows the formation of a much more diverse set of potential transition structures, which could be responsible for the propensity of hIAPP to form fibrils. Indeed, for both the 2-fold [113] and 3-fold [93] models for amylin, large β-sheets are present. Furthermore, residues 28 and 29, which had no observed strand content in rIAPP but occasionally formed β-sheets for hIAPP, are predicted to be part of the β-strands experimentally observed in hIAPP. These residues are in the β-sheet region of conformations identified as intermediates in the formation of amyloid fibrils [114]. The formation of a β-hairpin involving these atoms has also been identified as part of a transition from the α-helical to β-hairpin conformations of hIAPP [115].

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