Limits...
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

Fraction of structures with a helix (α-helix, 310 Helix or π Helix) or a strand (β-sheet or β-Bridge) for rIAPP (black symbols) and hIAPP (red symbols) as predicted with various force fields.Force field and solvent model combinations where the force field was optimized with that solvent model are shown with a filled symbol; otherwise an unfilled symbol is shown.
© Copyright Policy
Related In: Results  -  Collection

License
getmorefigures.php?uid=PMC4519342&req=5

pone.0134091.g004: Fraction of structures with a helix (α-helix, 310 Helix or π Helix) or a strand (β-sheet or β-Bridge) for rIAPP (black symbols) and hIAPP (red symbols) as predicted with various force fields.Force field and solvent model combinations where the force field was optimized with that solvent model are shown with a filled symbol; otherwise an unfilled symbol is shown.

Mentions: The free energy surfaces were used to calculate the fraction of amino acids in a helix (α-helix, 310 helix, or π-helix) or strand (β-sheet or β-bridge) as described above in the Methods section. The results at 310 K are shown in Fig 4 and span a range of helix and strand fractions. Depending on the force field, amylin can be found to adopt a helical structure with no β-sheet character, or a mostly random coil state with varying amounts of β-sheet structures. The force field which predicts the largest helical content for amylin is CHARMM22/CMAP with TIPS3P. Approximately 47% of amylin’s residues are predicted to be in an α-helix, 310 helix, or π-helix structure. This is not surprising, as this force field has been previously noted to exhibit a strong α-helical bias [28,42,43]. The force field predicting the second highest helical content is Amberff99sb*-ILDN with TIP3P (21%). Gromos96 53a6 predicts less than 0.5% helical content and the highest strand content, namely 11%. The next highest prediction of β-sheet content is by the OPLS-AA/L force field with TIP4P, which yields 9% helical content and 5% strand content.


Secondary Structure of Rat and Human Amylin across Force Fields.

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

Fraction of structures with a helix (α-helix, 310 Helix or π Helix) or a strand (β-sheet or β-Bridge) for rIAPP (black symbols) and hIAPP (red symbols) as predicted with various force fields.Force field and solvent model combinations where the force field was optimized with that solvent model are shown with a filled symbol; otherwise an unfilled symbol is shown.
© Copyright Policy
Related In: Results  -  Collection

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

pone.0134091.g004: Fraction of structures with a helix (α-helix, 310 Helix or π Helix) or a strand (β-sheet or β-Bridge) for rIAPP (black symbols) and hIAPP (red symbols) as predicted with various force fields.Force field and solvent model combinations where the force field was optimized with that solvent model are shown with a filled symbol; otherwise an unfilled symbol is shown.
Mentions: The free energy surfaces were used to calculate the fraction of amino acids in a helix (α-helix, 310 helix, or π-helix) or strand (β-sheet or β-bridge) as described above in the Methods section. The results at 310 K are shown in Fig 4 and span a range of helix and strand fractions. Depending on the force field, amylin can be found to adopt a helical structure with no β-sheet character, or a mostly random coil state with varying amounts of β-sheet structures. The force field which predicts the largest helical content for amylin is CHARMM22/CMAP with TIPS3P. Approximately 47% of amylin’s residues are predicted to be in an α-helix, 310 helix, or π-helix structure. This is not surprising, as this force field has been previously noted to exhibit a strong α-helical bias [28,42,43]. The force field predicting the second highest helical content is Amberff99sb*-ILDN with TIP3P (21%). Gromos96 53a6 predicts less than 0.5% helical content and the highest strand content, namely 11%. The next highest prediction of β-sheet content is by the OPLS-AA/L force field with TIP4P, which yields 9% helical content and 5% strand content.

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