title: Identification of putative unfolding intermediates of the mutant His-107-tyr of human carbonic anhydrase II in a multidimensional property space.
abstract: In this article, we develop an extensive search procedure of the multi-dimensional folding energy landscape of a protein. Our aim is to identify different classes of structures that have different aggregation propensities and catalytic activity. Following earlier studies by Daggett et al. [Jong, D. D.; Riley, R.: Alonso, D.O.: Dagett, V. J. Mol. Biol. 2002, 319, 229], a series of high temperature all-atom classical molecular simulation studies has been carried out to derive a multi-dimensional property space. Dynamical changes in these properties are then monitored by projecting them along a one-dimensional reaction coordinate, dmean . We have focused on the application of this method to partition a wide array of conformations of wild type human carbonic anhydrase II (HCA II) and its unstable mutant His-107-Tyr along dmean by sampling a 35-dimensional property space. The resultant partitioning not only reveals the distribution of conformations corresponding to stable structures of HCA II and its mutant, but also allows the monitoring of several partially unfolded and less stable conformations of the mutant. We have investigated the population of these conformations at different stages of unfolding and collected separate sets of structures that are widely separated in the property space. The dynamical diversity of these sets are examined in terms of the loading of their respective first principal component. The partially unfolded structures thus collected are qualitatively mapped on to the experimentally postulated light molten globule (MGL) and molten globule (MG) intermediates with distinct aggregation propensities and catalytic activities. Proteins 2016; 84:726-743. © 2016 Wiley Periodicals, Inc.
authors.affiliation: Department of Chemistry, Indian Institute of Technology, Kharagpur, 721302, India.
authors.forename: Puspita
authors.initials: P
authors.lastname: Halder
authors.affiliation: Department of Chemistry, Indian Institute of Technology, Kharagpur, 721302, India.
authors.forename: Srabani
authors.initials: S
authors.lastname: Taraphder
mesh_terms: D024402:Carbonic Anhydrase II / Q000737:chemistry* / Q000235:genetics; D020134:Catalytic Domain; D006801:Humans; D056004:Molecular Dynamics Simulation; D017354:Point Mutation; D066329:Protein Aggregates; D011487:Protein Conformation; D017433:Protein Structure, Secondary; D058767:Protein Unfolding
chemical_list: D066329:Protein Aggregates; D024402:Carbonic Anhydrase II
keywords: conformational clustering; high temperature; molecular dynamics; multi-dimensional property space analysis; principal component analysis; unfolding intermediates