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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

Free energy difference with coil for fraction of residues in a secondary structure predicted for rIAPP vs. time for Amberff99sb*-ILDN with TIP3P.The secondary structure of each residue was determined using DSSP.
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pone.0134091.g006: Free energy difference with coil for fraction of residues in a secondary structure predicted for rIAPP vs. time for Amberff99sb*-ILDN with TIP3P.The secondary structure of each residue was determined using DSSP.

Mentions: Fig 6 shows the free energy of rIAPP in a helix, strand, turn, and bend (relative to the coil) versus time for Amberff99sb*-ILDN with TIP3P. The free energy of the bend and turn states converges within approximately 100 ns, reaching a value that is 0.5 kT greater than the coil state. The helix and strand states take longer to converge. The difference in free energy between the helix and coil states starts small but grows to a maximum of 0.75 kT before slowly decreasing. At the end of the simulation the difference is 0.53 kT. The free energy difference between strand and coil increases rapidly until about 350 ns when it reaches a value of 3.8 kT. It then fluctuates around this value for the rest of the simulation, finishing at 3.9 kT. While the fraction of helix and possibly strand may not have completely converged even after 1000 ns, as evidenced by the small increase in fraction of helix, the differences are relatively unchanged after 350 ns. When these free energy differences are converted to fractions of the structure that are in a helix or strand versus time, they become even smaller and remain within 0.05 of the value at 100 ns. These fractions are the important weights when determining properties of the molecule, such as NMR shifts, hydrogen bonding, and chemical reaction rates. Small changes of less than 0.05 fraction of these structures will not greatly influence the results. Furthermore, these changes are small compared to the large differences between the force fields. The convergence plots for the other force fields are shown in S2 and S3 Figs for rIAPP and hIAPP respectively.


Secondary Structure of Rat and Human Amylin across Force Fields.

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

Free energy difference with coil for fraction of residues in a secondary structure predicted for rIAPP vs. time for Amberff99sb*-ILDN with TIP3P.The secondary structure of each residue was determined using DSSP.
© Copyright Policy
Related In: Results  -  Collection

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

pone.0134091.g006: Free energy difference with coil for fraction of residues in a secondary structure predicted for rIAPP vs. time for Amberff99sb*-ILDN with TIP3P.The secondary structure of each residue was determined using DSSP.
Mentions: Fig 6 shows the free energy of rIAPP in a helix, strand, turn, and bend (relative to the coil) versus time for Amberff99sb*-ILDN with TIP3P. The free energy of the bend and turn states converges within approximately 100 ns, reaching a value that is 0.5 kT greater than the coil state. The helix and strand states take longer to converge. The difference in free energy between the helix and coil states starts small but grows to a maximum of 0.75 kT before slowly decreasing. At the end of the simulation the difference is 0.53 kT. The free energy difference between strand and coil increases rapidly until about 350 ns when it reaches a value of 3.8 kT. It then fluctuates around this value for the rest of the simulation, finishing at 3.9 kT. While the fraction of helix and possibly strand may not have completely converged even after 1000 ns, as evidenced by the small increase in fraction of helix, the differences are relatively unchanged after 350 ns. When these free energy differences are converted to fractions of the structure that are in a helix or strand versus time, they become even smaller and remain within 0.05 of the value at 100 ns. These fractions are the important weights when determining properties of the molecule, such as NMR shifts, hydrogen bonding, and chemical reaction rates. Small changes of less than 0.05 fraction of these structures will not greatly influence the results. Furthermore, these changes are small compared to the large differences between the force fields. The convergence plots for the other force fields are shown in S2 and S3 Figs for rIAPP and hIAPP respectively.

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