Calix4arenes in mixed protic media: conformational characteristics and solvent effects captured with molecular simulations

Calix4arenes represent a group of synthetic macrocyclic compounds that can be suitably modified at both their upper and lower rims, allowing potential applications, including molecular recognition, antioxidant activity, and disease therapeutics. In particular, calix4tyrosol (CT) and aza-calix4tyrosol (ACT), originating from tyrosol units, have gained attention for their noted antioxidant properties. These systems are commonly synthesized in methanol, a solvent that exhibits significant bio-incompatibility. Elucidating their behavior in various media is, therefore, crucial for characterizing their behavior under biologically relevant conditions. In this study, we employ classical molecular dynamics simulations to investigate the solvation properties of CT and ACT in systematically varied methanol-water compositions. We investigate how the effective modulation of solvent polarity and dielectric constant influences solute-solvent interactions, along with interfacial structural and dynamic characteristics. Our systematic analyses indicate that the salient conformational characteristics of the considered calix4arenes are retained when water is introduced in the solvent media, across varying levels of effective dielectric constants. Structural, dynamic, and thermodynamic characterization of the environment lends molecular insights into solvation characteristics conducive to structural stability. This may be advantageous for applications requiring consistent conformational stability across different solvent environments. These results are relevant to the synthesis and deployment of calix4arene-based supramolecules and functional systems in aqueous media.