Modelling protein unfolding: hen egg-white lysozyme

A novel modelling procedure, which rapidly unfolds a protein by enhancing solvent penetration of its core, was used to investigate the unfolding pathway of hen egg-white lysozyme. Early on the unfolding pathway there is a dramatic disruption of the tertiary contacts within the protein, which decouples its domains. Subsequently, the helical domain slowly loses its compactness and the helices fluctuate rapidly. The protein then adopts a 'molten globule-like' structure in which the native beta-sheet is essentially intact. The modelled structures have properties similar to those of lysozyme's experimentally characterized partially folded states and provide insight into its complex (un)folding process. The sequence of unfolding events shows how the unfolding pathway of a multidomain protein may be most similar to its fastest, but not necessarily its dominant, folding pathway.