Insight Into The Interaction Mechanism Of Fullerene Derivatives In Regard To Thrombin: A Molecular Dynamics Study

In recent years,carbon nanomaterials have attracted the research interest of researchers in various fields due to their unique physicochemical properties and potential biological functions.The applications of nanoparticles in various fields such as biology,medicine and industry have been greatly expanded.Different nanoparticles can cause different biological effects because of their different characteristics.Manipulation of the structure of nanoparticles can help to regulate their physicochemical properties and even biological effects.For example,the introduction of functional groups such as –OH,-COOH,-NH2 on the surface of fullerenes would improve the surrounding hydrophilic-hydrophobic environment,thus adding new functions to nanomaterials.Compared with the traditional macro materials,nanomaterials have many functional advantages,which make the interdisciplinary of nano-science and biomedicine become the key research object in the emerging research field.Thrombin is the main target of antithrombotic and anticoagulant therapy.Although recent studies have shown that surface-modified fullerene derivatives can be used as novel nano-anticoagulants to effectively inhibit thrombin,the specific mechanism remains unclear.In this study,we investigated the binding mode and inhibition mechanism of fullerenes with thrombin by using various molecular modeling approaches.The results showed that owing to the hydrophobicity of the fullerene skeleton,the four existing fullerene inhibitors mainly combined with the active site of thrombin through van der Waals interaction and tended to make the surrounding environment hydrophobic.This made the inhibitors with hydrophobic side chains,especially those with large hydrophobic side chains containing benzene rings,have greater binding free energy with protein.However,for fullerenes with fewer hydrophilic side chains,it is difficult to change the surrounding hydrophobic environment.Van der Waals between the skeleton and protein remain the main contributor of binding free energy,with a smaller total binding free energy than that of inhibitors with hydrophobic side chains.However,as more hydrophilic groups can change the surrounding hydrophilic-hydrophobic environment and form more hydrogen bonds,the electrostatic contribution of the polyhydroxy side chain designed in this study was increased further.At the same time,the van der Waals interaction between the fullerene carbon skeleton and protein did not decrease significantly,resulting in a significantly increased total binding free energy and an enhanced inhibition effect.These findings provide a theoretical basis for the improvement of highly effective fullerene anticoagulants.