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ACID-UNFOLDING OF APOMYOGLOBIN
Compared to the native state, intermediate states on the protein folding/unfolding pathways are characterized by large structural fluctuations, which usually preclude resolution of the full structure of non-native states by X-ray crystallography or NMR. Under these circumstances, theoretical models may be the best alternative for elucidating their structural details. Using Molecular Dynamics simulations (MD) we model complete acid-induced unfolding of apomyoglobin -- the guinea pig in the experimental study of folding. The key point is that the simulation is at room temperature and models biologically relevant experimental conditions. No biasing potentials are used, the unfolding comes about naturally as a consequence of protonating the acidic side-chains.
Experimentally it is known that apo-myoglobin undergoes a two-phase unfolding, first to a molten globule intermediate (I-state) at about pH = 4, and finally to an unfolded state at pH = 2. In re-folding experiments, the I-state is shown to be an obligatory folding intermediate, suggesting strong similarity between acid-unfolding and re-folding pathways of apomyoglobin. We exploit this similarity to gain insight into the folding process of apomyoglobin.
>>>> Time course of the simulated acid-unfolding. >>>>
Note, that the completely acid-unfolded state retains some (~ 20%) residual secondary structure.
Some of our findings: