1887
banner image
No data available.
Please log in to see this content.
You have no subscription access to this content.
No metrics data to plot.
The attempt to load metrics for this article has failed.
The attempt to plot a graph for these metrics has failed.
α-helix to β-hairpin transition of human amylin monomer
Rent:
Rent this article for
USD
10.1063/1.4798460
/content/aip/journal/jcp/138/15/10.1063/1.4798460
http://aip.metastore.ingenta.com/content/aip/journal/jcp/138/15/10.1063/1.4798460
View: Figures

Figures

Image of FIG. 1.
FIG. 1.

Representative snapshots of human amylin peptide (a) in α-helical conformation, (b) in β-hairpin conformation, and (c) in unstructured coil state.

Image of FIG. 2.
FIG. 2.

(A) Free energy map for the different structures of the human amylin monomer along the order parameters α rmsd and β rmsd , as defined in Sec. II . The contour lines have been drawn at an interval of 2.5 kJ/mol, unless specified otherwise. Three low-energy states are labeled as (a) α-helical state, (b) β-hairpin state and (c) unstructured coil state. The black solid curve represents the minimum free energy path joining (a) to (b), calculated by a steepest descent algorithm. The solid and dotted red curves represent the minimum free energy path joining (a) to (c) and the minimum free energy path joining (c) to (b), respectively. The points in the inset of the figure represent transition paths from TPS simulations. Green points correspond to the zipping mechanism pathway between α-helical state and β-hairpin state. White points represent paths for the transition from the α-helical state to the unstructured coil state. Yellow points correspond to the transition pathways for folding from the unstructured coil state to the β-hairpin state. (B) Same as (A) but with results shown in expanded order parameter and energy scales. Roman numbers from (I) to (V) represent different states along the minimum free energy transition path for the zipping mechanism. The transition states for the pathways from α to β is denoted by T1, and for α to coil it is denoted by T2.

Image of FIG. 3.
FIG. 3.

Solvent accessible surface area (SASA) for the hydrophobic residue fragments (residues 16-17 and residues 23-27) as a function of time along the transition path for the zipping mechanism between α-helical and β-hairpin states (dotted black curve). The results have been averaged over 500 trajectories. For reference, a representative trajectory from TPS simulations is also shown in the figure in terms of its α-helical (solid red curve) and β-hairpin content (solid cyan curve). The encircled region represent the transition state ensemble. The configuration shown in the figure represents a typical transition state structure.

Image of FIG. 4.
FIG. 4.

Representative configurations of amylin showing hydrophobic residues LEU16, VAL17, PHE23, GLY24, ALA25, ILE26, and LEU27. (a) α-helical conformation, (b) intermediate conformation in which all the hydrophobic residues have collapsed, (c) intermediate conformation, when zipping along the turn region begins, and (d) β-hairpin conformation. The arrows in (a) show the direction of hydrophobic collapse that triggers the transition.

Image of FIG. 5.
FIG. 5.

Number of water molecules within 8 Å of side chains of PHE15 residue as a function of time along the transition path for the transition from the α-helical state to the unstructured coil state (solid black curve). The results have been averaged over 60 trajectories. For reference, a representative trajectory from TPS simulations is also shown in the Figure in terms of its α-helical content (dotted red curve). The encircled region represents the transition state ensemble and the configuration shown in the figure is representative of a transition state structure.

Image of FIG. 6.
FIG. 6.

Representative configurations of amylin showing hydrophobic residues PHE15. Panels (b)–(e) represent intermediate configurations for the transition from the α-helical state (a) to the unstructured coil state (f). The arrow in (a) shows the direction of rotation of PHE15 residue that triggers the transition.

Image of FIG. 7.
FIG. 7.

Free energy (ΔG) along the minimum free energy path connecting the α (χ = 0) and β (χ = 1) states using the zipping mechanism pathway. The horizontal axis (χ) corresponds to the fraction of total distance traveled along the minimum energy path shown by solid black line in Figure 2 . Roman numbers correspond to select points on the free energy map shown in the inset of Figure 2 . The configuration T1 corresponds to the transition state ensemble as obtained from TPS simulations. The activation energy (ΔG*), measured as the maximum free energy difference, is found to be 18.5 kJ/mol.

Image of FIG. 8.
FIG. 8.

Free energy along the minimum free energy path connecting the α (χ = 0) and unstructured coil (χ = 1) states. The horizontal axis (χ) corresponds to the fraction of total distance traveled along the minimum energy path shown by the solid red line in Figure 2 . The configuration T2 corresponds to the transition state ensemble as obtained from TPS simulations. The activation energy (ΔG*), measured as the maximum free energy difference, is found to be 26.4 kJ/mol.

Image of FIG. 9.
FIG. 9.

Summary of different folding pathways between the α-helical, the unstructured coil, and the β-hairpin states. In the first pathway (shown in blue), the transition occurs through a zipping mechanism, where there is a gradual loss of α-helical character accompanied by a gradual gain of β-hairpin character. The transition state is represented as T1. The reaction involves a hydrophobic collapse of residues 16-17 and 23-27. The typical time scale of the reaction is on the order of 10 ns in molecular dynamics simulations. The transition state ensemble was generated from 2.5 ns TPS simulations. In the second pathway (shown by red arrows), the transition occurs in two steps. First the α-helical state transforms to an unstructured coil state also within a time scale of approximately 10 ns. The transition state ensemble was determined from 2.5 ns TPS simulations. The transition state is represented as T2. The reaction involves the rotation of residue 15 from the solvent-rich region to the interior of the peptide. The second step involves a transition from the unstructured coil state to the β-hairpin state (dotted red); this latter process is diffusion limited and requires on the order of 300 ns in molecular dynamics simulations.

Loading

Article metrics loading...

/content/aip/journal/jcp/138/15/10.1063/1.4798460
2013-04-18
2014-04-24
Loading

Full text loading...

This is a required field
Please enter a valid email address
752b84549af89a08dbdd7fdb8b9568b5 journal.articlezxybnytfddd
Scitation: α-helix to β-hairpin transition of human amylin monomer
http://aip.metastore.ingenta.com/content/aip/journal/jcp/138/15/10.1063/1.4798460
10.1063/1.4798460
SEARCH_EXPAND_ITEM