Autonomous Directed Rotation of a Minimal Knotted Cyclopeptide

Knotted cyclopeptides have significant research value in the field of drug design due to their unique topological structures and superior stability. It is particularly noteworthy that they can convert individual atom thermal vibrations into a directed rotational motion of an entire molecule. Appling this property to the design of drug molecular scaffolds would greatly improve the probability of drug-Target binding and the efficiency of drug delivery systems. However, the minimal molecular complexity required to achieve this directed rotation and its core physical mechanism remain unclear. Therefore, we designed a trefoil knotted cyclopeptide chain composed of nine alanines (9-ALA), which is the shortest knotted cyclopeptide that can be constructed without atomic steric collision. Using all-Atom molecular dynamics simulations, we systematically studied its dynamic behaviors in both vacuum and explicit solvent. The results indicate that 9-ALA can achieve directed rotation of the entire molecule through atomic thermal vibrations in both environments, thereby establishing the minimal molecular complexity required for this phenomenon and verifying the physical mechanism that a simple topological knot is sufficient to convert disordered atomic thermal vibrations into ordered directed rotation of the molecule. Finally, we suggest 9-ALA as the minimal physical model for functionalized molecules. Combining the research framework of the "atomic vibration to molecule rotation"transformation mechanism with intelligent optimization algorithms, provides a new research perspective for design of functionalized knotted cyclopeptides with specific rotation.