Capturing the Supramolecular Association of Calixarenes onto Proteins Relying on Molecular Dynamics Simulations: The Case of Cytochrome C

Here, we propose a molecular dynamics investigation of the supramolecular association of sulfonatedcalix-[8]-arenes to cytochrome c. The binding sites prone to interactions with sulfonated calixarenescan be identified without prior knowledge of the X-ray structure, and the binding free energiesestimated by molecular mechanics Poisson-Boltzmann surface area (MM-PBSA) post-analysis arefound to be in neat agreement with the isothermal titration calorimetry (ITC) measurements The per-residuedecomposition reveals the detailed picture of this electrostatically-driven association and notably therole of the arginine R13 as a bridge residue between the two main anchoring sites. In addition,the analysis of the residue behavior by means of a supervised machine learning protocol unveils the formation of an hydrogen bond network far from the binding sites, increasing the rigidity of theprotein.