The Simulation Study On The Biocompatibility Of Low-dimensional Nanomaterials And Its Interaction With Biomolecules

In recent years,with the rapid development of nanotechnology,nanomaterials have been widely used in human life.They can interact with various biomolecules in human body,and display the bio-functions of nanomaterials.Molecular dynamics(MD)simulation method,as a theoretical direction and supplement for experimental section,has unique advantages in studying the interaction between nanomaterials and biomolecules at nanoscale and nanosecond level.Therefore,this academic dissertation mainly adopts MD simulation method to focus on the biocompatibility of low-dimensional nanomaterials(nanoparticles(NPs),nanosheet)and the interaction with biomolecules:(1)Using MD simulation method to study the biocompatibility of gold nanoparticles(AuNPs)and platinum nanoparticles(PtNPs),design relatively safe nano-drugs,and study their binding mechanisms with disease-related proteins(2)Using MD simulation method to study the biocompatibility of two-dimensional nanomaterials black phosphorus(BP),graphene nitride(C₂N)and graphene(GR)and the interaction mechanism with biomolecules.The main contents of each chapter are shown as follows:Chapter 1 IntroductionThis chapter introduce the classification of nanomaterials and the applications in biological system and the importance of nano-bio interaction in the research between nanomaterials and biomolecules.The molecular dynamics(MD)simulation method used in these studies,the main works and significance of this academic dissertation are summarized.Chapter 2 The study on biocompatibility of AuNPs and theoretical design of multi-CDRs-functional nanobodyModifying the surface of nanoparticles(NPs)with different biomolecules to enable them to have certain specific biological functions has become a hot spot in current research.This chapter studied the interaction between gold nanoparticles(AuNPs)and antigens hen egg white lysozyme(HEWL),epidermal growth factor receptor(EGFR)using molecular dynamics(MD)simulation.The results revealed that AuNPs had a good biocompatibility with antigens HEWL and EGFR,and was potential for further research in the biological area.Two types of complementary-determining regions(CDRs)in natural antibody were grafted onto AuNPs surface to design a novel multi-CDRs-functional nano-antibody.By means of the kinetic study between nano-antibody and antigen HEWL and EGFR,we found that the multi-CDRs-functional nano-antibody can spontaneously bind to both HEWL and EGFR,and this binding was stable but did not affect the underlying structure of antigens.Compared with the natural antibody,the affinity between multi-CDRs-functional nano-antibody and antigens was stronger.The nanobody design strategy proposed in this chapter can be used not only for antibody-antigen interactions,but also for interactions between various proteins.The research also provides an important theoretical basis for the design of nanobodies and nanomedicine.Chapter 3 The interaction between?-synuclein and n-MTAB AuNPs with different diameterThe aggregation of?-synuclein(?-syn)is one of the main causes of Parkinson's disease.While MTAB-AuNPs((16-Mercaptohexadecyl)Trimethyl Ammonium Bromide-Au nanoparticles)have the potential to inhibit?-syn aggregation.This chapter explore the binding mode between?-syn and n-MTAB AuNPs with different diameter(n denotes the number of CH2 in MTAB)by molecular dynamics(MD)simulation method.The results showed that the C-terminal and the NAC domain(a central hydrophobic non-amyloid?component)of?-syn can bind tightly to the n-MTAB AuNPs surface.The statistics and analysis of energy between?-synuclein and n-MTAB AuNPs indicated that the driving force of the binding between?-syn C-terminal and n-MTAB AuNPs was electrostatic interaction.We chose 5-MTAB AuNPs with the smallest particle size,MTAB AuNPs with the largest particle size and?-syn system as the main analysis and comparison objects.When?-syn interacted with 5-MTAB AuNPs,the potential hydrophobic force would weaken among?-syn proteins,which prevented?-syn from self-polymerization.In addition,the decomposition and compare of binding energy between?-syn and NPs found that the electrostatic interaction between?-syn and nanoparticles(NPs)didn't change along with the NPs size,which was the key factor of orientational binding between the?-syn C-terminal and n-MTAB AuNPs.The study lays a theoretical foundation for the study on the effect of the size of bio-functional NPs on the behavior of biomolecules on their surfaces.It also shows that 5-MTAB AuNPs are not only small in size,but also have the ability to inhibit the aggregation of?-syn.Chapter 4 Biocompatibility of novel PtNP-SOR and its molecular mechanism with VEGFR2The nano-drugs is modified by the short peptide have also better biocompatibility,but its target is not obvious.Based on the anisotropy of PtNPs,we first proposed a new type of nano-drugs PtNP-sorafenib(PtNP-SOR).By means of molecular dynamics simulation,the stability and biocompatibility of PtNP-SOR were investigated.The interaction mechanism of PtNP-SOR and vascular endothelial growth factor receptor 2(VEGFR2)was explored and compared with that of the peptide 2a coated PtNPs(PtNP-2a).The results showed that PtNP-SOR could bind to VEGFR2 more stably,which was driven by the Coulombic(Coul)and strong dispersion interaction between PtNP-SOR and VEGFR2.According to their contributions to the binding free energies,the key residues in VEGFR2 were identified to form the specific space,which increased the affinity with PtNP-SOR.This research provides new insights for the design of PtNP drugs,as well as the important theoretical proof of the interaction between PtNP-SOR and VEGFR2 at the molecular level,which has certain reference significance for the development and optimization of new nano-drugs.Chapter 5 The adsorption behavior of two typical protein on BP,C₂N and GR surfacesThe biotoxicity of nanomaterials is very important for the application of nanomaterials in biomedical systems.This chapter employed proteins with varying secondary structures(?-helices,?-sheets,and mixed?/?structures)to investigate the biological properties of three representative two-dimensional(2D)nanomaterials;these nanomaterials consisted of black phosphorus(BP),graphene(GR),and nitrogenized graphene(C₂N)and were studied using molecular dynamics(MD)simulations.The results showed that the?-helix motif underwent a slight structural change on the BP surface and little structural change on the C₂N surface.In contrast,the structure of the?-sheet motif remained fairly intact on both the BP and C₂N surfaces.The?-helix and?-sheet motifs were able to freely migrate on the BP surface,but they were anchored to the C₂N surface.In contrast to BP and C₂N,GR severely disrupted the structures of the?-helix and?-sheet motifs.BBA protein with mixed?/?structures adsorbed on the BP and C₂N surfaces and exhibited biological behaviors that were consistent with those of the?-helix and?-sheet motifs.In summary,C₂N may possess better biocompatibility than BP and GR and is expected to have applications in the biomedical field.This study not only comprehensively evaluated the biological characteristics of nanomaterials but also provided theoretical strategy to explore and distinguish the surface characteristics of nanomaterials.Chapter 6 The effect of BP nanosheets on the combination of SARS-CoV-2 S RBD and ACE2Severe acute respiratory syndrome coronavirus 2(SARS-CoV-2)Spike(S)glycoprotein binding to host angiotensin-converting enzyme 2(ACE2)is the main pathway that leads to the infection of serious coronavirus disease 2019(COVID-19),and thus SARS-CoV-2 S glycoprotein becomes an important target for many inhibitors.With the application of nanomaterials in biomedical field,black phosphorus(BP)nanosheets have caused more attention owing to its excellent characteristics.This chapter studied the biological effect of BP to the interaction between SARS-CoV-2 S and ACE2.The results indicated that ACE2 could quickly and stably adsorb on the BP surface by a non-specific interaction due to its larger size.The structural integrity of ACE2 was remained,which implied that the normal bio-function of ACE2 was not affected.When the defined receptor-binding domain(RBD)in SARS-CoV-2 S protein bound to ACE2 adsorbed on the BP surface,the interaction between RBD and ACE2 is greatly weakened such as hydrogen bonds,salt bridge and van der waals force.This study not only indicated that BP had a good biocompatibility,but also revealed that BP itself could effectively obstruct the binding of SARS-CoV-2 S glycoprotein and ACE2,which may provide a potential and reasonable drug carrier to raise the curative effect of inhibitors against SARS-CoV-2 infection.