Abstract
Simple SummaryThe integrin αvβ3-RGD motif interaction plays a key role in the progression of malignant tumor. Although two typical cyclic and linear RGD short peptides have been widely used in tumor diagnosis and therapy, little is known about the internal dynamic mechanism for different configurations of RGD peptides with different affinities interacting with the integrin αvβ3. Our results showed that the cyclic RGD peptide had a more stable configuration in binding to integrins αvβ3, which depended on the higher binding energy and higher static electrical energy, especially in the interaction between AspRGD-MIDAS. The steered molecular dynamics simulation showed a stronger interaction for the cyclic RGD-integrin αvβ3 system than the linear one, with a larger dissociation force (average peak force) and more time to dissociate. Our findings provide insights into the dynamics of integrin αvβ3 interactions with linear and cyclic RGD ligands and offer some new therapeutic approaches for the design and development of novel antitumor drugs.Integrin αvβ3 interacting with the short Arg-Gly-Asp (RGD) motif plays a critical role in the progression of several types of tumors. However, the effects of the RGD structure (cyclic or linear) with integrin αvβ3 at the atomic level remain poorly understood. Here, we performed association and dissociation dynamic simulations for integrin αvβ3 in complex with a linear or cyclic pentapeptide by steered molecular dynamics simulations. Compared with cyclic RGD, the linear RGD peptide triggers instability of the configurational changes, mainly resting with the RGD domain due to its flexibility. The main interaction energy between Mg2+ and cyclic RGD is much stronger than that of the linear RGD system by the well shield to lessen attacks by free water molecules. The force-dependent dissociation results show that it is easier for linear RGD peptides to leave the active site and much quicker than the cyclic RGD ligand, whereas it is harder to enter the appropriate active binding site in linear RGD. The Ser123-AspRGD bond may play a critical role in the allosteric pathway. Our findings provide insights into the dynamics of αvβ3 interactions with linear and cyclic RGD ligands and contribute to the application of RGD-based strategies in preclinical therapy.
Highlights
Tumor angiogenesis, the formation of new blood vessels, is a critical process for tumor growth and metastasis [1,2,3]
Integrin αvβ3 plays a crucial role in angiogenesis and tumor metastasis, which is widely expressed in many kinds of human tumor biopsy samples but not in vessels in normal tissues [6,7]
The corresponding structural stability and energy fluctuation profiles were obtained. These results provide insights into the differences in the dynamic properties of RGD-containing peptides with the integrin objective, which will help better understand the field of RGD-mediated drug delivery and imaging constructs
Summary
The formation of new blood vessels, is a critical process for tumor growth and metastasis [1,2,3]. Among cell adhesion molecules (CAMs), integrins are important CAMs that link the extracellular matrix (ECM) and the cytoskeleton and participate in adhesive events during various cancer stages, such as tumor growth, invasion, and metastasis [5]. Integrin αvβ plays a crucial role in angiogenesis and tumor metastasis, which is widely expressed in many kinds of human tumor biopsy samples but not in vessels in normal tissues [6,7]. The use of RGD-modified peptides to inhibit the activity of integrin αvβ is a promising strategy for tumor targeting
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