Li Na, Qiu Simei, Fang Ying, Wu Jianhua, Li Quhuan
School of Bioscience and Bioengineering, South China University of Technology, Guangzhou 510006, China.
Guangdong Provincial Engineering and Technology Research Center of Biopharmaceuticals, South China University of Technology, Guangzhou 510006, China.
Biology (Basel). 2021 Jul 20;10(7):688. doi: 10.3390/biology10070688.
Integrin αβ 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 αβ at the atomic level remain poorly understood. Here, we performed association and dissociation dynamic simulations for integrin αβ 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 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-Asp bond may play a critical role in the allosteric pathway. Our findings provide insights into the dynamics of αβ interactions with linear and cyclic RGD ligands and contribute to the application of RGD-based strategies in preclinical therapy.
与短的精氨酸 - 甘氨酸 - 天冬氨酸（RGD）基序相互作用的整合素αβ在多种肿瘤的进展中起着关键作用。然而，在原子水平上，RGD结构（环状或线性）与整合素αβ的相互作用效果仍知之甚少。在此，我们通过引导分子动力学模拟对整合素αβ与线性或环状五肽复合物进行了缔合和解离动力学模拟。与环状RGD相比，线性RGD肽引发构象变化的不稳定性，主要是由于其灵活性而导致RGD结构域不稳定。通过良好的屏蔽作用以减少游离水分子的攻击，Mg与环状RGD之间的主要相互作用能比线性RGD系统强得多。力依赖的解离结果表明，线性RGD肽更容易离开活性位点，且比环状RGD配体快得多，而线性RGD更难进入合适的活性结合位点。丝氨酸 - 天冬氨酸键可能在变构途径中起关键作用。我们的研究结果为αβ与线性和环状RGD配体相互作用的动力学提供了见解，并有助于基于RGD的策略在临床前治疗中的应用。
