Fig 1.
Structural details of the insulin molecule.
(A) The structure of the insulin (PDB ID: 2G4M). A-Chain (orange); B-chain N-terminal (residues F1–G8) (red), B-chain α-helix (residues S9–C19) (black), B-chain C-terminal (residues G20–T30) (blue). The colored spheres represent the Cα atoms of the first and last residues of the A and B-chains. (B) The new ribbon representation shows the hydrophobic core of insulin, comprising the residues F24, L15, Y26, L11, V12, G8 (side chains shown in cyan), I2A and V3A (side chains shown in green). The hydroxyl group of Y26 and the oxygen atom of G8 are shown in red, and the disulfide bridges in yellow. (C) The hydrogen bonds between the residues neighboring Y24 and the A chain residues, G23(O)–N2A(N) and F25(N)–Y19A(O), are illustrated in blue dashed lines. Oxygen and nitrogen atoms are represented in red and blue, respectively.
Table 1.
The BC-CT and B-chain α-helix residues used to characterize the dynamics of the BC-CT.
Fig 2.
RMSDs of six MD simulations of insulin.
The first five MD simulations have a duration of 120 ns, while the sixth one 90 ns. The RMSDs are given with respect to the crystal structure 2G4M.
Table 2.
The strong interactions in the hydrophobic core that are responsible for maintaining insulin in its closed conformation.
Fig 3.
Time series of the distances between the Cα atoms of Y26–V12 and P28–G8.
These distances are used as a criterion for the opening of the BC-CT and activation of insulin.
Fig 4.
Distribution of the distances between the Cα atoms of Y26–V12 and P28–G8.
The different histogram colors correspond to the different conformations of the BC-CT, namely, closed (black), open (cyan) and wide-open (blue).
Fig 5.
(A) The PMFs as a function of the distance between the pairs shown in Table 1. (B) Illustration of the pairs. The spheres in blue and red represent the Cα atoms of the BC-CT and B-chain α-helix residues, respectively.
Fig 6.
The zipper-like opening of the BC-CT with a hinge at F24.
The BC-CT in its closed and open conformations is shown in blue and green, respectively. The colored spheres represent the Cα atoms of the corresponding residues.
Fig 7.
Entry of water molecules as a criterion of the BC-CT opening.
Correlation between the number of water molecules within the hydrophobic core (red) and the opening of the BC-CT, i.e. the Y26(Cα)-V12(Cα) distance (blue), for two randomly chosen intervals of the long MD simulation. (A) 90–120 ns and (B) 210–240 ns.
Fig 8.
Effect of Y26 mutations on the BC-CT opening.
The distance between the Cα atoms of the Y26–V12 residues, which determines the criterion for the BC-CT opening, for the Y26G, Y26A, Y26N and Y26F mutations. The closed conformation distance in WT insulin is shown for reference (black dashed line).
Table 3.
Probabilities of the closed, open, and wide-open conformations of the BC-CT for WT and mutated insulin.
Fig 9.
Distances between the Cα atoms of the F24–L15 and Y26–V12 pairs, which represent the hinge and the BC-CT opening, respectively, for the WT (blue) and the mutated (red) insulin, after the hinge is broken and the protein is in its wide-open conformation. The trajectories are compared to the closed conformation distance of WT insulin (black dashed line).