Comparison of Linear vs. Cyclic RGD Pentapeptide Interactions with Integrin αvβ3 by Molecular Dynamics Simulations

Authors：Li, Na; Qiu, Simei; Fang, Ying; Wu, Jianhua; Li, Quhuan^*

Source：Biology-Basel, 2021, 10(7): 688.

DOI：10.3390/biology10070688

• integrin alpha(v)beta(3)
• RGD peptide
• force-induced dissociation
• molecular dynamics simulations

Simple Summary The integrin alpha(v)beta(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 alpha(v)beta(3). Our results showed that the cyclic RGD peptide had a more stable configuration in binding to integrins alpha(v)beta(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 alpha(v)beta(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 alpha(v)beta(3) interactions with linear and cyclic RGD ligands and offer some new therapeutic approaches for the design and development of novel antitumor drugs. @@@ Integrin alpha(v)beta(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 alpha(v)beta(3) at the atomic level remain poorly understood. Here, we performed association and dissociation dynamic simulations for integrin alpha(v)beta(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 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 Ser(123)-Asp(RGD) bond may play a critical role in the allosteric pathway. Our findings provide insights into the dynamics of alpha(v)beta(3) interactions with linear and cyclic RGD ligands and contribute to the application of RGD-based strategies in preclinical therapy.

• Institution
  中国科学院