Dynamics of the Primary Processes of Protein Folding: Helix Nucleation

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Abstract

We report on the folding and unfolding dynamics of α-helix nucleation in two model helical peptides. One of the peptides studied unfolds at lower temperatures (cold denatures) in solutions of 9% hexafluoroisopropanol. Laser-induced temperature jumps were used to rapidly perturb the helix/coil equilibrium in this peptide from a predominantly unfolded to a more folded ensemble. The peptide conformation was monitored through time-resolved absorption of the amide I‘ band. These experiments directly probe α-helix nucleation, as a majority of α-helices formed must start from a completely random coil conformation. In another α-helical peptide, the unfolding and folding kinetics of specific residues were monitored through the use of isotopically (13CO) labeled amino acids. By selectively measuring the unfolding kinetics of the middle of the helix, one can minimize the contribution of end-fraying effects and explicitly probe the crossing of a nucleation free energy barrier in the helix to coil direction. The results reveal that α-helix nucleation occurs on a sub-microsecond time-scale with a substantial enthalpic barrier.

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