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

Predicted Cα secondary chemical shifts for Amberff99sb*-ILDN with TIP3P, Amberff03w with TIP4P2005, CHARMM22* with TIPS3P, CHARMM22/CMAP with TIPS3P, Gromos96 53a6 with SPC, and OPLS-AA/L with TIP4P.The predictions were made using SPARTA+.
© Copyright Policy
Related In: Results  -  Collection

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

pone.0134091.g007: Predicted Cα secondary chemical shifts for Amberff99sb*-ILDN with TIP3P, Amberff03w with TIP4P2005, CHARMM22* with TIPS3P, CHARMM22/CMAP with TIPS3P, Gromos96 53a6 with SPC, and OPLS-AA/L with TIP4P.The predictions were made using SPARTA+.

Mentions: The NMR secondary shifts were computed for amylin and compared with the experimental results from Williamson and Miranker [106]. These were calculated for the Cα, Cβ, Hα, HN, and N atoms. The random coil shifts from SPARTA+ [110] were used for these calculations. These random coil shifts were subtracted from the chemical shifts obtained by Williamson and Miranker in order to compare secondary shifts calculated using the same random coil shifts. The Cα secondary shifts provide a measure of the secondary structure propensity of the residue; a value greater than 0 suggests a propensity towards helical structures; a value of 0 indicates a random coil structure, and values less than 0 correspond to β-sheet structures. The Cα secondary shifts are shown in Fig 7 for several force field and water combinations. Amberff99sb*-ILDN with TIP3P qualitatively reproduces the major trends in the chemical shift pattern. Residues 5–25 are up-shifted, corresponding to the increased α-helical propensity. It also captures the down field secondary shifts around the glycine and first proline. The agreement with the experimental results is the poorest at the C-terminus. The values predicted are higher than the experimental chemical shifts, corresponding to a slight propensity in the simulations to form a small α-helix at the C-terminus. Most experimental evidence suggests that this region is predominantly unstructured. Because random coil regions involve a large number of low energy states their sampling is challenging and prone to statistical uncertainties, which may explain the differences between the predicted and experimental results. Fig 7 shows a similar result for Amberff03w with TIP4P2005 and CHARMM22* with TIPS3P: the discrepancy between the predicted and experimental NMR results is greatest in the disordered C-terminus of rIAPP.


Secondary Structure of Rat and Human Amylin across Force Fields.

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

Predicted Cα secondary chemical shifts for Amberff99sb*-ILDN with TIP3P, Amberff03w with TIP4P2005, CHARMM22* with TIPS3P, CHARMM22/CMAP with TIPS3P, Gromos96 53a6 with SPC, and OPLS-AA/L with TIP4P.The predictions were made using SPARTA+.
© Copyright Policy
Related In: Results  -  Collection

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

pone.0134091.g007: Predicted Cα secondary chemical shifts for Amberff99sb*-ILDN with TIP3P, Amberff03w with TIP4P2005, CHARMM22* with TIPS3P, CHARMM22/CMAP with TIPS3P, Gromos96 53a6 with SPC, and OPLS-AA/L with TIP4P.The predictions were made using SPARTA+.
Mentions: The NMR secondary shifts were computed for amylin and compared with the experimental results from Williamson and Miranker [106]. These were calculated for the Cα, Cβ, Hα, HN, and N atoms. The random coil shifts from SPARTA+ [110] were used for these calculations. These random coil shifts were subtracted from the chemical shifts obtained by Williamson and Miranker in order to compare secondary shifts calculated using the same random coil shifts. The Cα secondary shifts provide a measure of the secondary structure propensity of the residue; a value greater than 0 suggests a propensity towards helical structures; a value of 0 indicates a random coil structure, and values less than 0 correspond to β-sheet structures. The Cα secondary shifts are shown in Fig 7 for several force field and water combinations. Amberff99sb*-ILDN with TIP3P qualitatively reproduces the major trends in the chemical shift pattern. Residues 5–25 are up-shifted, corresponding to the increased α-helical propensity. It also captures the down field secondary shifts around the glycine and first proline. The agreement with the experimental results is the poorest at the C-terminus. The values predicted are higher than the experimental chemical shifts, corresponding to a slight propensity in the simulations to form a small α-helix at the C-terminus. Most experimental evidence suggests that this region is predominantly unstructured. Because random coil regions involve a large number of low energy states their sampling is challenging and prone to statistical uncertainties, which may explain the differences between the predicted and experimental results. Fig 7 shows a similar result for Amberff03w with TIP4P2005 and CHARMM22* with TIPS3P: the discrepancy between the predicted and experimental NMR results is greatest in the disordered C-terminus of rIAPP.

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