The Effect of Electrostatic Interactions on the Folding Kinetics of a 3-α-Helical Bundle Protein Family

The trio of protein segment repeats called spectrins diverges by more than 2 orders of magnitude in their folding and unfolding rates, despite having very similar stabilities and almost coincidental topologies. Experimental studies revealed that the mutation of five particular residues dramatically alters the kinetic rates in the slow folders, making them similar to the rates of the fast folder. This is considered to be an exceptional behavior which seems in principle to challenge the current understanding of the protein folding process. In this work, we analyze this scenario, using a simplified computational model, combined with state-of-the-art kinetic analysis techniques. Our model faithfully separates the kinetics of the fast and slow folders and captures the effect of the five mutations. We show that the inclusion of electrostatics in the model is necessary to explain the experimental findings.