Conformational Flexibility Is a Determinant of Permeability for Cyclosporin.
J Phys Chem B
; 122(8): 2261-2276, 2018 03 01.
Article
en En
| MEDLINE
| ID: mdl-29400464
ABSTRACT
Several cyclic peptides have been reported to have unexpectedly high membrane permeability. Of these, cyclosporin A is perhaps the most well-known example, particularly in light of its relatively high molecular weight. Observations that cyclosporin A changes conformation depending on its solvent environment led to the hypothesis that conformational dynamics is a prerequisite for its permeability; however, this hypothesis has been difficult to validate experimentally. Here, we use molecular dynamics simulations to explicitly determine the conformational behavior of cyclosporin A and other related cyclic peptides as they spontaneously transition between different environments, including through a lipid bilayer. These simulations are referenced against simulations in explicit water, chloroform, and cyclohexane and further validated against NMR experiments, measuring conformational exchange, nuclear spin relaxation, and three-dimensional structures in membrane-mimicking environments, such as in dodecylphosphocholine micelles, to build a comprehensive understanding of the role of dynamics. We find that conformational flexibility is a key determinant of the membrane permeability of cyclosporin A and similar membrane-permeable cyclic peptides, as conformationally constrained variants have limited movement into, then through, and finally out of the membrane in silico. We envisage that a better understanding of dynamics might thus provide new opportunities to modulate peptide function and enhance their delivery.
Texto completo:
1
Colección:
01-internacional
Base de datos:
MEDLINE
Asunto principal:
Ciclosporina
Idioma:
En
Revista:
J Phys Chem B
Asunto de la revista:
QUIMICA
Año:
2018
Tipo del documento:
Article
País de afiliación:
Australia