Study On The Interaction Between The Metallofullerenol And Cytochrome Enzymes

With the rapid development of nanotechnology,research of new nanomaterials is more and more strategic.Nanomaterials exhibit vigorous vitality in the field of biomedicine,and their biosafety needs further study.Nanomaterials are bound to interact with biological macromolecules in living organisms and affect life.The effects of change of free energy and reconstruction of biomolecules on the surface of nanomaterials are not fully understood.In general,the interaction between nanomaterials and biomolecules occurs at nanoscale level.The time ranges from picosecond to microsecond.Therefore,it is difficult to study the interaction between nanomaterials and biomolecules through wet experiments.As a supplement of experimental methods,molecular dynamics simulation has a unique advantage in describing the interaction between nanomaterials and biomolecules in such a time and space scale.Here we use molecular dynamics simulations to study the potential interaction between nanomaterials and biological macromolecules such as proteins.The metallofullerenol Gd@C82(OH)22 is regarded as a potential anti-tumor therapeutic due to its metastasis inhibition in numerous experiments.As a promising nanodrug,the toxicity of Gd@C82(OH)22 requires thorough assessment before substantial clinical application.In the present study,we focus on the interaction between Gd@C82(OH)22 and the cytochrome P450(CYP)enzyme CYP2C8.CYP2C8 can metabolize more than 60 clinically-used drugs as well as numerous endogenous compounds and hence is a potential target for nanotoxicity.By using all-atom molecular dynamics simulations and free energy calculations,we observe that Gd@C82(OH)22 nanoparticles bind favorably to the B-C and F-G loops that are substrate recognition sites(SRS)in CYPs.Moreover,binding on these two loops blocks the openings of the channels 2b,2e and 4.These are the most common channels that allow substrates to access and egress from the deeply buried heme active site.We find that this binding event is largely driven by the electrostatic interactions,with the induced negative charge on the surface of Gd@C82(OH)22 interacting favorably with the positively charged B-C and F-G loops.In addition,based on the molecular dynamics simulation,the binding processes of Gd@C82(OH)22 onto the three channels are analyzed.It is indicated that the aggregation of Gd@C82(OH)22 molecules is an important factor for blockage of the CYP2C8 channels.The Gd@C82(OH)22 may affect or inhibit the normal function of the CYP2C8 by inactivating the substrate entry and exit channel and/or disrupting the substrate recognition sites.The interaction between cytochrome CYP and metalfullerenol is worthy for further study.