Formation of electrostatic interactions on the protein-folding pathway

Biochemistry
M Oliveberg, A R Fersht

Abstract

We describe a novel method of obtaining information about the structures of transient conformations on the folding pathway from their ionization equilibria: the H+ -titration behavior of a protein residue is determined in detail by its environment. We follow the consolidation of electrostatic interactions in the folding process by comparing the acid-titration behavior of four conformations on the folding pathway of barnase: the denatured state (D); the folding intermediate (I); the major transition state(+); and the native state (N) in the scheme D <==>I<==>(+)<==)N. The results show that strong electrostatic interactions are present in the major transition state: some of its carboxylate groups display the highly anomalous pKA values of <2 that are found in N. However, the network of ionic surface interactions is not formed in (+), and the overall protection of titrating residues is weakened. The results are consistent with the transition state being an expanded form of the native state, with a weakened but poorly hydrated core and a loosened periphery. The surface residues in such an expanded conformation are, on average, farther apart than are those in the center of the molecule. The results concerning the folding intermediat...Continue Reading

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