Journal of Chemical Sciences

, Volume 129, Issue 7, pp 1031–1044 | Cite as

Unfolding intermediates of the mutant His-107-Tyr of human carbonic anhydrase II

  • Srabani Taraphder
  • Puspita Halder
  • Tanmoy Kumar Paul
  • Satyajit Khatua
Regular Article


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.


Carbonic anhydrase unfolding marble brain disease mutant folding intermediates 



A part of this work has been funded by Council of Scientific and Industrial Research (CSIR), India, Grant number: 01(2485)/11/EMR-II. All computational studies were carried out using the high performance computing facility at Department of Chemistry, IIT Kharagpur, funded by DST-FIST (SR/FST/CSII-011/2005), India. Research fellowships from UGC, India (TKP) and IIT Kharagpur (SK) are gratefully acknowledged.


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Copyright information

© Indian Academy of Sciences 2017

Authors and Affiliations

  1. 1.Department of ChemistryIndian Institute of TechnologyKharagpur, West BengalIndia

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