Abstract
Cyclophilin from Leishmania donovani (LdCyp) is a ubiquitous peptidyl-prolyl cis-trans isomerase involved in a host of important cellular activities, such as signaling, heat shock response, chaperone activity, mitochondrial pore maintenance and regulation of HIV-1 infectivity. It also acts as the prime cellular target for the auto-immune drug cyclosporine A (CsA). LdCyp is composed of a beta barrel encompassing the unique hydrophobic core of the molecule and is flanked by two helices (H1, H2) on either end of the barrel. The protein contains a lone partially exposed tryptophan. In the present work the equilibrium unfolding of LdCyp has been studied by fluorescence, circular dichroism and the non-coincidence of their respective Cm's, indicates a non-two state transition. This fact was further corroborated by binding studies of the protein with bis-ANS and the lack of an isochromatic point in far UV CD. The thermal stability of the possible intermediates was characterized by differential scanning calorimetry. Further, MD simulations performed at 310, 400 and 450K exhibited the tendency of both helices to partially unwind and adopt non-native geometries with respect to the core, quite early in the unfolding process, in contrast to the relatively stable beta barrel.
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