Witek, Jagna, Keller, Bettina G., Blatter, Markus, Meissner, Axel, Wagner, Beatrix and Riniker, Sereina (2016) Kinetic Models of Cyclosporin A in Polar and Apolar Environments Reveal Multiple Congruent Conformational States. Journal of Chemical Information & Modeling, 56 (8). pp. 1547-1562. ISSN 1549-960X

Abstract

The membrane permeability of cyclic peptides and peptidomimetics, which are generally larger and more complex than typical drug molecules, is likely strongly influenced by the conformational behavior of these compounds in polar and apolar environments. The size and complexity of peptides often limit their bioavailability, but there are known examples of peptide natural products such as cyclosporin A (CsA) that can cross cell membranes by passive diffusion. CsA is an undecapeptide with seven methylated backbone amides. Its crystal structure shows a "closed" twisted beta-pleated sheet conformation with four intramolecular hydrogen bonds that is also observed in NMR measurements of CsA in chloroform. When binding to its target cyclophilin, on the other hand, CsA adopts an "open" conformation without intramolecular hydrogen bonds. In this study, we attempted to sample the complete conformational space of CsA in chloroform and in water by molecular dynamics simulations in order to better understand its conformational behavior in these two environments and to rationalize the good membrane permeability of CsA observed experimentally. From 10 mus molecular dynamics simulations in each solvent, Markov state models were constructed to characterize the metastable conformational states. The model in chloroform is compared to nuclear Overhauser effect NMR spectroscopy data reported in this study and taken from the literature. The conformational landscapes in the two solvents show significant overlap but also clearly distinct features.

Item Type:	Article
Additional Information:	Unmapped bibliographic data: LA - English [Field not mapped to EPrints] ST - Kinetic Models of Cyclosporin A in Polar and Apolar Environments Reveal Multiple Congruent Conformational States [Field not mapped to EPrints] AU - Witek, J. [Field not mapped to EPrints] AU - Keller, B. G. [Field not mapped to EPrints] AU - Blatter, M. [Field not mapped to EPrints] AU - Meissner, A. [Field not mapped to EPrints] AU - Wagner, T. [Field not mapped to EPrints] AU - Riniker, S. [Field not mapped to EPrints] J2 - J Chem Inf Model [Field not mapped to EPrints] AD - Witek,Jagna. Laboratory of Physical Chemistry, ETH Zurich , Vladimir-Prelog-Weg 2, 8093 Zurich, Switzerland. [Field not mapped to EPrints] DB - MEDLINE [Field not mapped to EPrints] DP - Ovid Technologies [Field not mapped to EPrints] AN - 27387150 [Field not mapped to EPrints]
Date Deposited:	25 Jan 2017 00:45
Last Modified:	25 Jan 2017 00:45
URI:	https://oak.novartis.com/id/eprint/29294