Posted by Natural antimicrobial peptides are a promising new class of antibiotics that offer a potential response to the growing challenge of microbial resistance. Among these, lipopeptides─cationic peptides conjugated with fatty acid residues─are especially noteworthy as their tendency to form α-helical structures plays a crucial role in determining their biological effectiveness. The ability to adopt an ordered structure, which directly influences their antimicrobial action, is determined by the length of the conjugated alkyl chain. In this study, experimental methods (isothermal titration calorimetry and circular dichroism), complemented by in silico analysis, have been successfully applied to rigorously characterize the interactions between three types of cyclodextrin (α-, ß-, and γ-) and three variants of antimicrobial KR12-lipopeptides, namely, the octanoylated (C8-KR12-NH2), laurylated (C12-KR12-NH2), and myristoylated (C14-KR12-NH2) KR12-lipopeptide. This integrated approach allowed, for the first time, the extraction of detailed structural and dynamic insights into the mechanism by which KR12 guests insert into the cyclodextrin cavity host. Furthermore, it was proven that encapsulation of the hydrophobic chain within the cyclodextrin cavity disrupts intramolecular interactions stabilizing the α-helical structure, leading to a reduced content of α-helicity. These findings underscore the role of cyclodextrins as modulators of the structural and functional properties of α-helical lipopeptides.
Martyna Kapica, Ola Grabowska, Elżbieta Kamysz, Julia Kamysz, Sergey A. Samsonov, and Dariusz Wyrzykowski (2026) Cyclodextrin and KR12-Lipopeptide Interactions: A Thermodynamic View of Binding Mechanisms and Impact on the Structure of α-Helical Peptides. The Journal of Physical Chemistry B 130 (4), 1167-1174. https://doi.org/10.1021/acs.jpcb.5c06749