Comparison of Linear vs. Cyclic RGD Pentapeptide Interactions with Integrin α(v)β(3) by Molecular Dynamics Simulations

SIMPLE SUMMARY: The integrin α(v)β(3)-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 α(v)β(3). Our results showed that the cyclic RGD peptide had a more stable configuration in binding to integrins α(v)β(3), which depended on the higher binding energy and higher static electrical energy, especially in the interaction between Asp(RGD)-MIDAS. The steered molecular dynamics simulation showed a stronger interaction for the cyclic RGD-integrin α(v)β(3) 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 α(v)β(3) interactions with linear and cyclic RGD ligands and offer some new therapeutic approaches for the design and development of novel antitumor drugs. ABSTRACT: Integrin α(v)β(3) 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 α(v)β(3) at the atomic level remain poorly understood. Here, we performed association and dissociation dynamic simulations for integrin α(v)β(3) 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 Mg(2+) 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 Ser(123)-Asp(RGD) bond may play a critical role in the allosteric pathway. Our findings provide insights into the dynamics of α(v)β(3) interactions with linear and cyclic RGD ligands and contribute to the application of RGD-based strategies in preclinical therapy.