Temperature-dependent conformational transitions and hydrogen-bond dynamics of the elastin-like octapeptide GVG(VPGVG): a molecular-dynamics study

Abstract

A joint experimental/theoretical investigation of the elastin-like octapeptide GVG(VPGVG) was carried out. In this article a comprehensive molecular-dynamics study of the temperature-dependent folding and unfolding of the octapeptide is presented. The current study, as well as its experimental counterpart (see companion article in this issue) find that this peptide undergoes an inverse temperature transition (ITT), leading to a folding at approximately 40-60 degrees C. In addition, an unfolding transition is identified at unusually high temperatures approaching the normal boiling point of water. Due to the small size of the system, two broad temperature regimes are found: the ITT regime at approximately 10-60 degrees C and the unfolding regime at approximately T > 60 degrees C, where the peptide has a maximum probability of being folded at T approximately 60 degrees C. A detailed molecular picture involving a thermodynamic order parameter, or reaction coordinate, for this process is presented along with a time-correlation function analysis of the hydrogen-bond dynamics within the peptide as well as between the peptide and solvating water molecules. Correlation with experimental evidence and ramifications on the properties of elastin are discussed.

FIGURE 1

Time evolution of selected structural quantities of GVG(VPGVG) in water at 330 K. (a) Distance from C- to N-terminus, r_C–N; (b) radius of gyration, r_gyr; (c) radius of gyration of the valine side chains, ; (d) number of peptide-peptide HBs, n_pp; (e) number of water molecules bridging two amino acids of peptide by HBs, n_bw; (f) number of HBs between peptide and solvating water molecules, n_ps; and (g) projection of the trajectory onto the first eigenvector of the covariance matrix, ; see text for definitions. For presentation purposes only, the functions were denoised using the Savitzky-Golay procedure (Savitzky and Golay, 1964), where a time window of 128 ps and a polynomial of sixth degree was used; the analysis was, however, carried out based on the original data sets.

FIGURE 2

Graphical representation of typical protein conformations at 330 K including only bridging waters; (a) open state and (b) closed state.

FIGURE 3

Time evolution of selected structural quantities of GVG(VPGVG) in water at 300 K. (Top) Radius of gyration, r_gyr; (middle) number of water molecules in first solvation shell of hydrophilic backbone atoms, n_bb; and (bottom) number of water molecules in first solvation shell of hydrophobic side chain atoms, n_sc. See Fig. 1 for smoothing procedure.

FIGURE 4

Average quantities as a function of temperature. (a) Distance from C- to N-terminus, r_C–N, •; (b) radius of gyration, r_gyr, ▪; (c) radius of gyration of valine side chains, , ▾; (d) number of HBs between peptide and solvating water molecules, n_ps, ▴; (e) number of internal HBs, n_IHB, ♦; and (f) number of water molecules solvating a backbone heavy atom, n_bb, ▸; and number of water molecules solvating a hydrophobic side-chain atom, n_sc, ◂; see text for definitions. Dashed lines are linear connections of the data to guide the eye. Solid lines are linear least-squares fit.

FIGURE 5

Results of the principal component analysis. (a) Visualization of large amplitude opening and closing mode, m₁. (b) Visualization of large amplitude librational mode, m₂. (c) Distribution function of the projection at 280, 330, 360, and 390 K. (d) Distribution function of the projection at 280, 330, 360, and 390 K. (e) Relative free energy along the projection . (f) Relative free energy along the projection . In a and b, an artificial trajectory using the full first m₁ (a), and second m₂ (b), eigenvector was synthesized for a suitable graphical presentation. In e–f: 280 K, □; 330 K, ▵; 380 K, ⋄; and 390 K, ○. For presentation purposes the free energy profiles for 330, 380, and 390 K were shifted in energy by 5, 10, and 15 kJ mol⁻¹, respectively.

FIGURE 6

Dynamics of the m₁ eigenmode. (a) Autocorrelation function, c_m(t), at 280 K, □; 330 K, ▵; 360 K, ⋄; and 390 K, ○. (b) Relaxation time τ_m as a function of temperature; here the symbol size reflects approximate error bars, ○. (c) Peptide backbone quasiharmonic entropy, S, ▿, as a function of temperature; see text for definitions.

FIGURE 7

Temperature- and time-dependence of various HB autocorrelation functions, c(t): HBs between (a) water molecules in the bulk, c_w(t); (b) first shell solvation water molecules and bulk water molecules, c_sw(t); (c) the peptide and first shell solvation water molecule, c_ps(t); and (d) direct HB contacts of the peptide with itself, c_pp(t) (see text for definitions). The choice of contour lines is coded in each panel as a, b, and c, where a and c denote the lowest and the highest contours, respectively, and b defines the relative spacing.

FIGURE 8

Temperature- and time-dependence of various HB autocorrelation functions, n(t): HBs between (a) water molecules in the bulk, n_w(t), and (b) the peptide and first shell solvation water molecules, n_ps(t). See text for definitions. The choice of contour lines is coded in each panel as a, b, and c, where a and c denote the lowest and the highest contours, respectively, and b defines the relative spacing.

FIGURE 9

Arrhenius plot of rate constants for HB breaking, k, and reformation, , for HBs between (a) first shell protein solvation water molecules and bulk water molecules, k_sw,▿; first shell protein solvation water molecules around the hydrophilic side chains, k_sc, ▵; water molecules in the bulk, k_w, ◃, and , ▴; (b) the peptide and first shell solvation water molecules, k_ps, ⋄; and , ♦; (c) the peptide with itself, k_pp, ○. The symbol size covers the error bars and the lines are linear (i.e., Arrhenius) fits; see text for definitions and Table 1 for the resulting fit parameters.