Molecular Dynamics Simulations On The Interaction Between Carbon-based Nanomaterials And Biological Molecules

With the further research of nanomaterials,carbon based nanomaterials have wide application prospects in material chemistry,information science,energy materials and other fields due to their outstanding physical and chemical properties.In recent years,it has been found that carbon nanomaterials can achieve efficient drug delivery and intelligent targeting.Therefore,it is considered to be a potential material in the biological field of drug delivery and cancer treatment.However,due to carbon nanomaterials entering the body in various forms,its potential biological toxicity cannot be underestimated.Some researchers believe that the chemical activity of carbon nanomaterials to produce reactive oxygen species?ROS?is an important reason for its toxicity,and experiments and simulations show that the interactions between nanomaterials and biological macromolecules?such as proteins,nucleic acids?are also one of the ways in which they produce toxicity.They can adsorb to proteins and even bind to the hydrophobic core sites of proteins,causing their loss of biological activity.Therefore,to understand of the interaction mechanism between carbon-based nanomaterials and bio-macromolecules is the basis for studying non-toxic and biocompatible nanomaterials.Fullerene molecules are typical zero-dimensional carbon nanomaterials,which have high reactivity and can easily penetrate cell membranes.However,due to their highly hydrophobic surface,they aggregates form clusters easily.The surface modification of hydrophilic groups?-NH₂ and-OH,etc.?can improve their water solubility and reduce biological toxicity.Fullerene-based molecules are considered as potential inhibitors of protein tyrosine phosphatases due to their unique properties and low toxicity.However,the underlying molecular mechanism remains elusive.In this study,molecular dynamics?MD?simulations in conjunction with molecular docking calculations were utilized to investigate the binding effects of C₆₀,C₆₀?NH₂?₃₀,and C₆₀?OH?₃₀ on the enzymatic activity of CD45?a receptor-like protein tyrosine phosphatase?.Our results show that all the investigated molecules can be docked into the region between D1 and D2 domains of CD45,where the binding pocket of C₆₀ is significantly different from the latter two due to its high hydrophobicity.The average number of residues directly interact with the C₆₀?NH₂?₃₀ is two more than that of C₆₀?OH?₃₀,F819 and F820?locate in the loop connects?3 and?12?,resulting in different effects of C₆₀?NH₂?₃₀ and C₆₀?OH?₃₀ on protein activity.Detailed MD simulation analyses show that transformation of the interaction network caused by C₆₀?NH₂?₃₀ is completely different from that of the control simulation due to the misfolding of?3.Furthermore,the movement of D1 active pocket and KNRY motif are most severely impaired by docking with C₆₀?NH₂?₃₀.Our simulation results illustrate that fullerene derivatives modified with amino group exhibit conspicuous tumor inhibition to protein tyrosine phosphatases,and can act as effective inhibitors.Our results give insight into the inhibitory effects of fullerenebased molecules on protein tyrosine phosphatases and providing theoretical basis for the design of effective inhibitors.Single-walled carbon nanotube is a widely used two-dimensional carbon nanomaterials,which has great research value in many fields such as biomaterials.Carbon nanotubes have extremely low solubility in aqueous solutions and organic solvents,so it aggregates easily.Recently,researchers have found that aggregated single wall carbon nanotubes have a more significant effect on methamphetamine addiction than single carbon nanotubes by injecting carbon nanotubes into mice.But the mechanism is still unknown.By using all-atom molecular dynamics simulations,we investigate the effects of single and aggregated SWCNTs?single?10,10?CNT,aggregated-7-?10,10?CNTs and single?35,35?CNT with same diameter as the aggregated one?on the activity of Tyrosine hydroxylase?Tyr OH?.TyrOH can catalyze the conversion of tyrosine to levodopa,controlling the ratedetermining step of the catecholamine synthesis pathway.The simulation results show that TyrOH can adsorb on these three kinds of carbon nanotubes,and the binding affinity is enhanced with the increase of diameter.Single?10,10?CNTs have less effect on the overall protein structure and the active pocket conformation.The?35,35?CNTs completely deactivate the stability of the overall protein structure due to the large contact area.Aggregate7-?10,10?CNTs can maintain the stability of the protein secondary structure due to the existence of more interstitial water around it.However,it changes the conformation of the active pocket and reduces the binding affinity of native substrate pterin in the active pocket.Thus it is more effective enough to inhibit the enzyme activity of TyrOH.Dopamine transporter?DAT?is a highly conserved transmembrane protein.The mechanism of its action is to utilize the electrochemical gradient inside and outside the cell membrane to achieve reuptake of dopamine molecules.Abnormal function of DAT can cause an unusual increase in the concentration of dopamine in the body,which is a symptom of addiction.The interaction between carbon nanotubes and DAT was investigated by molecular dynamics simulation.Our results show that 7-?10,10?CNTs change the"gate mechanism"of DAT and maintain an“outward-facing”conformation,which is conducive to the reuptake of dopamine.The two single carbon nanotubes keep“extracellular gate”in a closed state.[3H]-WIN35428 is an effective inhibitor of dopamine reuptake.Its binding affinity with DAT is severely damaged by the adsorption of 7-?10,10?CNTs,thereby enhancing the transport capacity of dopamine.Our findings provide explanation for the interaction between proteins and different carbon nanotubes,elucidating the mechanism of aggregated carbon nanotubes for treating drug addiction.Graphene is a kind of carbon nanomaterial composed of sp2 carbon atoms,and its thickness is only 0.34 nm,which is sufficient for the detection of single amino acid or nucleic acid.Therefore,it has become a popular material for the detection of single molecules.We studied the translocation of thioredoxin?Trx?through graphene nanopores with different diameters and charges by using steered molecular dynamics simulation?SMD?,and calculated the current by applying an external electric field.The results of SMD simulations show that when the nanopore pore size is small?1 nm?,the amino acids translocate through the pores one by one under the external force,and the translocation of charged amino acids can be judged by the peak of the pull force F,providing further identification of individual amino acids.At a pore size of 1.4 nm,it can be observed that Trx has a distinct multistep translocation characteristic:the region?A108-L58?is easily translocated---starting at the translocation of K57,the formation of a"kink"between the?2/?3/?B blocks the nanopore--the"kink"opens as the translocation of K18,and protein translocation is completed.At a pore size of 2 nm,intermediate states such as“kink”can also be observed,but due to insufficient space resistance,the protein cannot be completely unfolded.We further investigated the application of 1 nm pore size graphene nanopores in protein sequencing.As the amount of charge in the nanopore increases,the translocation rate of Trx also slows down,which is very important for the sequencing work.By calculating the current difference between charged nanopores or neutral nanopores,we find that the time at which the peak of the curve appears corresponds to the translocation of negatively charged amino acids,and the valleys correspond to the translocation of positively charged amino acids.Although only positively and negatively charged amino acids can be detected qualitatively,it also means that charged graphene nanopores have potential for application in protein sequencing.In this thesis,we used full-atomic molecular dynamics simulations,molecular docking,and steered molecular dynamics methods to systematically investigate the interaction modes between fullerenes,carbon nanotubes,graphene and different biological macromolecules?proteins?.The mechanism of their effect on protein activity and application potential in the field of biological device manufacture are discussed.