The Kinetics Mechanism Of The Cyclic Vs. Linear RGD Sequence Peptides With Integrin ?_v?₃

At present,since the incidence of malignant tumor and its mortality is gradually increased every year,it has become a heavy burden in low-and middle-income families.Therefore,it is an urgent task to find out the ways to effectively treat malignant tumor,and study about the development of malignant tumor has become the research focus.Integrin plays an important role in some pathological process such as the invasion and metastasis of malignant tumor,wound healing and inflammation through mediated by cell and cell,and cells and extracellular matrix.Among integrin,?_v?₃ is one of the important members of the integrin family.It's reported that integrin ?_v?₃ is widely expressed on the surface of a variety of malignant tumor cells and vascular endothelial cells,and plays a critical roles in tumor angiogenesis.Consequently,integrin ?_v?₃ has become one of the important targets for tumor diagnosis and treatment.For the preferential and specific binding to integrin ?_v?₃,the RGD peptides labeled with radioactive nuclide were used as imaging or drug carrier which have been widely applied in the related medical field of imaging constructs and drug delivery.At present,the RGD-containing peptides are mainly designed into two different steric conformation: cyclic and linear.The affinity of RGD-containing peptides with integrin ?_v?₃ may be affected by steric conformation of the peptides that can directly affect the therapeutic effect of antitumor drug.To elucidate the mechanism of how the steric conformation of the RGD-containing peptides to affect the interaction between RGD peptides with integrin ?_v?₃,molecular dynamics simulation was used in this study to build the experiment models: the cyclic?RGDfV?and the linear RGDf V ligated with integrin ?_v?₃,respectively,and the structure mechanism of two different steric conformational RGD-containing ligands interact with ?_v?₃ was analyzed.The results showed that the binding stability of the linear RGD peptides ligated with integrin ?_v?₃ was much weaker than the cyclization,due to its flexibility that not only easy to interact with the surrounding residues around the receptor,but also can form intramolecular hydrogen bonds.Furthermore,it also found that compared with the linear RGD-containing peptides,the kinetic energy barrier between the Asp^RGD-MIDAS in the cyclization was much greater,which may be one of the reason why the cyclic RGD-containing peptides ligated with integrin ?_v?₃ are more stable.In the blood flow of fluid environment,the interaction between integrin ?_v?₃ and RGD-containing short peptides is a force-chemical coupling biological processes.It is not only regulated by the chemical properties of the molecular but also the blood flows.It.This study used steered molecular dynamics simulation to reveal how the tensile force to regulate the bonding strength between integrin ?_v?₃ and RGD-containing ligands at the atomic level.It was found that there were two major force peaks during the dissociation between integrin ?_v?₃ and RGD ligands,correspond to two important residues pairs,Arg^RGD-Asp²¹⁸ and Asp^RGD-MIDAS,respectively.Compared with that of the linear RGD-containing peptides,the rupture force was greater during the cyclic RGD peptide were pulling away from integrin ?_v?₃,while the disrupting time was longer.This suggests that the binding affinity between the cyclic RGD peptide and integrin ?_v?₃ are more potent.While in the process of the association between integrin ?_v?₃ and RGD-containing peptides,compared with the linear RGD ligands,the interaction energies between the cyclic RGD ligands with the receptor was much stronger,and the distance of the important residues pairs Asp^RGD-MIDAS was closer.The above experiment showed that the binding properties between the cyclic RGD peptide and integrin ?_v?₃ are more stable.Compared with the linear RGD ligands,the cyclization is employed to improve the binding properties with integrin ?_v?₃.In summary,this study was mainly focused on the structural and dynamic mechanism of integrin ?_v?₃ interacting with different steric conformation of RGD-containing peptides,and to explore how the steric conformation affect the stability and affinity between RGD-containing peptides with integrin ?_v?₃.It was confirmed that the cyclization could improve the binding stability and properties of RGD-containing peptides ligated with integrin ?_v?₃.The results of this study contribute to better understanding how the different steric conformation affecting the interaction between the RGD-containing sequence with integrin ?_v?₃,and offer effective guidance for the design and development of new antitumor drugs.