Insight Into The Interaction Mechanism Of Carbon Nanomaterials In Regard To AChE:A Molecular Dynamics Study

Carbon nanomaterials have attracted great interest from researchers in many fields,due to its unique physical structure and potential chemical properties.Nanoparticles can carry drug molecules in vivo,especially the hollow structure of carbon nanotubes is more conducive to the transport of drug molecules.At the same time,the functional development of nanomaterials has broad prospects,for example,the functional groups of-OH,-COOH,-NH₂ as the side chains and aromatic rings in fullerenes or carbon nanotubes will increase the new function of nanomaterials,whose functional groups can improve the surrounding hydrophilic-hydrophobic environment.Compared with traditional macro materials,nanomaterials have more obvious advantages.Interdisciplinary research in nanoscience and other fields has also become a research focus in emerging fields.In the fields of biomedicine,the fullerene and its derivatives are mostly widely used of the nanomaterial fields.For example,a novel inhibitor of HIV protease is a fullerene derivative having a good inhibitory effect.And according to that research,a recent research found that several modified fullerene compounds are excellent inhibitors for Acetylcholinesterase?AChE?despite of the unclear inhibitory mechanism.Meanwhile,Acetylcholinesterase is an important kind of esterase that plays a key biological role in the central and peripheral nervous system.Recent research has demonstrated that some fullerene derivatives serve as a new nanoscale-class of potent inhibitors of AChE,but the specific inhibition mechanism remains unclear.In the present article,several molecular modeling methods,such as moleculardocking,moleculardynamicssimulations,andmolecular mechanics/generalized Born surface area calculations,were used for the investigation of the binding mode and inhibition mechanism of fullerene inhibitions for AChE.Results revealed that fullerene inhibitors block the entrance of substrates by binding with the peripheral anionic site?PAS?region.On the one hand,description that the inhibitor was finally induced to move toward the gorge region by the strong hydrophobic interactions of conserved residues.On the other hand,the movement of inhibitor pulls the?loop and the acyl pocket moving together with it through the interactions of inhibitor with Tyr72,Asp74,Leu76 on the?loop and Trp286,Leu289,Pro290,Ser293 on the acyl pocket.Thus,fullerene derivatives might mainly serve as competitive inhibitors.The–interactions of a fullerene backbone with AChE are at the same level in different single side chain systems and seem to be related to the length or aromaticity of the side chain.The inhibitor with multi hydroxyl side chains shows an obviously large electrostatic interaction as it forms additional hydrogen bonds with AChE.Moreover,fullerene derivatives might exhibit noncompetitive inhibition partly by affecting some secondary structures around them.Thus,the destructions of these secondary structures can lead to conformational changes in some important regions,such as the catalytic triad and acyl pocket.The investigation is of great importance to the discovery of good fullerene inhibitors.In addition,we also used molecular dynamics simulation methods to investigate the effect of carbon nanotubes and carbon nanotubes with hydrophobic groups?-NH₂?and hydrophilic groups?-OH?on the inhibition of acetylcholinesterase.It was found that the addition of a hydrophobic group?-NH₂?and a hydrophilic group?-OH?changed the pro-hydrophobic environment of the enzyme,allowing the inhibitor to be more deeply embedded in the active region.By combining the calculation of free energy,we also found that the decomposition free energy of Tyr72,Asp74 and Leu76contributed a lot,and these residues are located on the?loop,indicating that the?loop interacts with the inhibitor to block the entry of the substrate.Therefore,it has a good suppression effect.In summary,the interaction mechanism of nanomaterials in biological systems studied by molecular dynamics simulation and other means can provide theoretical guide for the biological application as well as improvement of carbon nanomaterials.