Molecular Basis For The Targeted Binding Of RGD-containing Peptides To Integrinα_νβ₃

Malignant tumor has always been one of the major threats to human life. It is a constant exploration and practice direction for experts in medical field, which is constantly developing new anticancer drug delivery system and improving the effect of drug targeting and treatment. Integrins are an important kind of adhesion molecules, which regulate cell signal transduction of inside and outside through configuration or expression levels change, thus influence the interactions between cells, cells and extracellular matrix, then ultimately affect the growth, survival, differentiation and apoptosis of tumor cells. Integrin αvβ3is an important member of the integrin family, which plays an important role in the process of tumor angiogenesis. Arginine-Glycine-Aspartate-containing (Arg-Gly-Asp, RGD) three peptides can specifically combine with integrin αvβ3. RGD-based vectors have been applied in tumor angiogenesis imaging and therapy research. The research on the mechanisms of interaction between RGD-containing peptides and integrin αvβ3at the molecular level can guide the design and development of vector materials. Therefore, it has a very important practical significance.Molecular dynamics simulations were performed to study the dynamic process of RGD-containing peptides binding to integrin αvβ3at the molecular level. The effects of structure and quantity of RGD-containing peptide, and RGD-containing peptides modifying chitosan oligosaccharide on this interaction mechanism with integrin αvβ3were analyzed at the molecular level.1. Specific binding activity was mainly driven by the electrostatic interactions between residues and metal ions. In addition, salt bridges, water bridges, hydrogen bond and the Van der Waals interactions also played a supporting role in the binding of RGD-containing peptide to integrin αvβ3.2. Because of the flexible structure of the linear RGD-containing peptide, its ability of combining with integrin αvβ3is not markedly better than that of the cyclic RGD-containing peptide. 3. An increase in the number of RGD-containing peptides can improve the probability of the combination with integrin αvβ3, but there are also some disadvantages, the interactions between RGD-containing peptides can hinder RGD binding to integrin αvβ3. The optimal molar concentration ratio of RGD peptides to integrin αvβ3appeared to be2:1. Because there are multiple binding sites on integrin αvβ3, it is possible that two RGD-containing peptides can bind to the same integrin αvβ3.4. When chitosan oligosaccharide is modified by the different number of cyclic RGDFD peptides, the two RGDFD peptides are best for the combination with integrin αvβ3.Then on this basis, in order to closer to the actual experiment condition, reduce system size, a preliminary study on the combining of multiple cyclic RGDFV peptides and multiple segments of integrin αvβ3was performed. The main driving force in the target recognition is still electrostatic interactions, Van der Waals interactions supplemented. During100ns, there exited slightly clustering among integrins αvβ3. According to the initial positions of six cyclic RGDFV peptides, their situations of combining with integrin αvβ3are different, but the combination mode is the same as the single integrin αvβ3.These results provide a deeper understanding of the interaction mechanism between RGD-containing peptides and integrin αvβ3at the molecular level, and are significant in improving the application prospects of RGD-based vectors in tumor imaging and targeted drug delivery of anti-angiogenic therapy.