Kinetic Models of Cyclosporin A in Polar and Apolar Environments Reveal Multiple Congruent Conformational States

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 β-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 μs 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.