Protein tertiary structure and the myoglobin phase diagram

Abstract

We develop an effective theory approach to investigate the phase properties of globular proteins. Instead of interactions between individual atoms or localized interaction centers, the approach builds directly on the tertiary structure of a protein. As an example we construct the phase diagram of (apo)myoglobin with temperature (T) and acidity (pH) as the thermodynamical variables. We describe how myoglobin unfolds from the native folded state to a random coil when temperature and acidity increase. We confirm the presence of two molten globule folding intermediates, and we predict an abrupt transition between the two when acidity changes. When temperature further increases we find that the abrupt transition line between the two molten globule states terminates at a tricritical point, where the helical structures fade away. Our results also suggest that the ligand entry and exit is driven by large scale collective motions that destabilize the myoglobin F-helix.

Figure 1

Comparison between simulated (sperm whale) value ${\mathcal{Q}}_{\alpha }$ that counts the relative number of residues in α-helical posture, and experimentally determined (horse heart) α-helical content during thermal denaturation. Experimental data is adapted from.

Figure 2

(Dis)ordering temperatures for the eight helices A-H at μ = 0, in terms of deviations in torsion angles from their α-helical values. Note that helix-F becomes disordered at relatively low temperature.

Figure 3

The R_g phase diagram: Collapsed native state (N), (dis)ordering of F-helix (F), two molten globules (I_a and I_b) and random coil (U) phase are identified. Note the presence of an apparent tricritical point, when the transition line between I_a and I_b terminates in U.

Figure 4

The evolution of R_g at temperature close to T = 0 °C. The native state, the state with disordered F-helix and the two molten globule states I_a and I_b are all identifiable.

Figure 5

The phase diagram in terms of the observable ${\mathcal{Q}}_{\alpha }$ that counts the relative number of residues in α-helical posture, at low temperatures T < 40 °C.