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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, ╬▒-helices, and ╬▓-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 ╬▒-helix and ╬▓-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 ╬▓-hairpins, while CHARMM22/CMAP predicts structures that are overly ╬▒-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 rat amylin as a function of ╬▒RMSD and ╬▓RMSD for various force fields.The darker regions indicate regions of lower free energy.
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pone.0134091.g001: Free energy of rat amylin as a function of ╬▒RMSD and ╬▓RMSD for various force fields.The darker regions indicate regions of lower free energy.

Mentions: The free energy of rIAPP as a function of ╬▒RMSD and ╬▓RMSD is shown in Fig 1 for various combinations of force fields and water models. Amberff03w with TIP4P is shown in S1 Fig. Note that ╬▒RMSD and ╬▓RMSD are proportional to the number of residues in the respective secondary structure; a larger value of ╬▒RMSD indicates that a larger fraction of rIAPP is in an ╬▒-helical state. Once the ╬▒RMSD increases beyond approximately 3 units, ╬▒-helices exist in a majority of structures. Likewise, ╬▓-sheets exist in most structures with a ╬▓RMSD greater than approximately 2 units. The color of the plots provides the magnitude of the free energy in kJ/mol. Significant qualitative differences between many of the force fields considered here are immediately apparent. Most force fields favor a predominantly random coil, with the deepest local minima below 3 ╬▒RMSD and 2 ╬▓RMSD. However, CHARMM22/CMAP heavily favors ╬▒-helical structures, with a deep minimum around 16 RMSD. In contrast, Gromos96 53a6 favors ╬▓-hairpin structures: its deepest minimum occurs around 0.5 ╬▒RMSD and 2.5 ╬▓RMSD. The Amberff99sb*-ILDN force fields predict predominantly random coil structures. However, the ╬▒-helical and ╬▓-hairpin structures are not completely disfavored, and significant fractions of amylin exist in both states. Amberff03w with TIP4P2005 is almost completely disordered. There are no local minima in the ╬▒-helical or ╬▓-hairpin states. CHARMM22* with TIPS3P exhibits a deep minimum at 1 ╬▒RMSD and 0.5 ╬▓RMSD, well within the random coil region. The OPLS-AA/L force field exhibits a qualitatively different free energy surface from those of the other force fields, with long ╬▒-helical and 2 ╬▓-hairpin structures being highly disfavored. It is, however, less ╬▒-helical and more heavily ╬▓-hairpin than Gromos96 53a6 with SPC. Importantly, these free energy differences are substantial and lead to qualitatively different conclusions regarding the pathways for amyloid formation.


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 rat amylin as a function of ╬▒RMSD and ╬▓RMSD 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.g001: Free energy of rat amylin as a function of ╬▒RMSD and ╬▓RMSD for various force fields.The darker regions indicate regions of lower free energy.
Mentions: The free energy of rIAPP as a function of ╬▒RMSD and ╬▓RMSD is shown in Fig 1 for various combinations of force fields and water models. Amberff03w with TIP4P is shown in S1 Fig. Note that ╬▒RMSD and ╬▓RMSD are proportional to the number of residues in the respective secondary structure; a larger value of ╬▒RMSD indicates that a larger fraction of rIAPP is in an ╬▒-helical state. Once the ╬▒RMSD increases beyond approximately 3 units, ╬▒-helices exist in a majority of structures. Likewise, ╬▓-sheets exist in most structures with a ╬▓RMSD greater than approximately 2 units. The color of the plots provides the magnitude of the free energy in kJ/mol. Significant qualitative differences between many of the force fields considered here are immediately apparent. Most force fields favor a predominantly random coil, with the deepest local minima below 3 ╬▒RMSD and 2 ╬▓RMSD. However, CHARMM22/CMAP heavily favors ╬▒-helical structures, with a deep minimum around 16 RMSD. In contrast, Gromos96 53a6 favors ╬▓-hairpin structures: its deepest minimum occurs around 0.5 ╬▒RMSD and 2.5 ╬▓RMSD. The Amberff99sb*-ILDN force fields predict predominantly random coil structures. However, the ╬▒-helical and ╬▓-hairpin structures are not completely disfavored, and significant fractions of amylin exist in both states. Amberff03w with TIP4P2005 is almost completely disordered. There are no local minima in the ╬▒-helical or ╬▓-hairpin states. CHARMM22* with TIPS3P exhibits a deep minimum at 1 ╬▒RMSD and 0.5 ╬▓RMSD, well within the random coil region. The OPLS-AA/L force field exhibits a qualitatively different free energy surface from those of the other force fields, with long ╬▒-helical and 2 ╬▓-hairpin structures being highly disfavored. It is, however, less ╬▒-helical and more heavily ╬▓-hairpin than Gromos96 53a6 with SPC. Importantly, these free energy differences are substantial and lead to qualitatively different conclusions regarding the pathways for amyloid formation.

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, ╬▒-helices, and ╬▓-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 ╬▒-helix and ╬▓-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 ╬▓-hairpins, while CHARMM22/CMAP predicts structures that are overly ╬▒-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