LAUSR

The mutant His-107-Tyr of human carbonic anhydrase II (HCA II) is highly unstable and has long been linked to a misfolding disease known as carbonic anhydrase deficiency syndrome (CADS). High temperature unfolding trajectories of the mutant are obtained from classical molecular dynamics simulations and analyzed in a multi-dimensional property space. When projected along a reaction coordinate these trajectories yield four distinguishable sets of structures that map qualitatively to folding intermediates of this mutant postulated earlier from experiments. We present in this article a detailed analysis of representative structures and proton transfer activity of these intermediates. It is also suggested that under suitable experimental conditions, these intermediates may be distinguished using circular dichroism (CD) spectroscopy.Graphical Abstract.  We present a novel computational methodology of extracting representative structures of putative unfolding intermediates of a large protein from high temperature classical MD simulations. The extracted structures are investigated to assess their aggregation propensity and projected catalytic activity.