Studying the Geometry and Dynamics of Prospective Parkinson-Inhibitor MCoCP4 Variants with Modified Grafting Topologies

Cyclotides are special knotted proteins stabilized by three pairs of disulfide bonds. Onto such a molecule as the scaffolding, small peptides can be grafted, with some specific conformations and new functions emerging as a result of this grafting. Thus, there is experimental evidence that the molecule MCoCP4, obtained by grafting a linear derivative of the CP4 Parkinson inhibitor CLATWAVG onto loop 6 of the cyclotide MCoTI-I, can possibly reduce to a greater extent the cytotoxicity of α-synuclein and has therefore better chances as a therapeutic alternative against the Parkinson disease. In this study, we extend this grafting strategy to the cyclotide MCoTI-II, which is highly homologous with MCoTI-I. We analyze the dynamical and geometrical properties of this specific grafted molecule, as well as two variants with differing grafting topologies, using molecular dynamics (MD) simulations. By visualizing the local geometry in discrete Frenet Frames (DFF) along the trajectory, we analyze the impact of the grafting point on the behaviour of the CP4-derived grafts. We quantify the backbone twisting and the sidechain orientation in all three scaffolds by calculating the folding index and the orientation of the C_β atoms in the DFF formalism. For each grafting topology, we obtain a representative structure for the CP4-derived graft. We discuss the possibility of the obtained results giving rise to a ranking scheme aiming at optimisation of the desired biological effect of the so-engineered molecule.