Comparison of Linear vs. Cyclic RGD Pentapeptide Interactions with Integrin α(v)β(3) by Molecular Dynamics Simulations.
Comparison of Linear vs. Cyclic RGD Pentapeptide Interactions with Integrin α(v)β(3) by Molecular Dynamics Simulations.
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通过分子动力学模拟比较线性与环状 RGD 五肽与整合素 alpha(v)beta(3) 的相互作用
DOI：
10.3390/biology10070688
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发表时间：
2021-07-20
期刊：
影响因子：
4.2
通讯作者：
Li Q
中科院分区：
文献类型：
--
作者：
Li N;Qiu S;Fang Y;Wu J;Li Q
整合素αvβ3 - RGD模体相互作用在恶性肿瘤进展中起关键作用。尽管两种典型的环状和线性RGD短肽已广泛用于肿瘤诊断和治疗，但对于不同亲和力的不同构型RGD肽与整合素αvβ3相互作用的内在动力学机制知之甚少。我们的结果表明，环状RGD肽在与整合素αvβ3结合时具有更稳定的构型，这取决于更高的结合能和更高的静电能，特别是在AspRGD - MIDAS之间的相互作用中。导向分子动力学模拟显示，环状RGD - 整合素αvβ3系统的相互作用比线性系统更强，具有更大的解离力（平均峰值力）和解离所需的更长时间。我们的发现为整合素αvβ3与线性和环状RGD配体相互作用的动力学提供了见解，并为新型抗肿瘤药物的设计和开发提供了一些新的治疗方法。
整合素αvβ3与短的精氨酸 - 甘氨酸 - 天冬氨酸（RGD）模体相互作用在几种类型肿瘤的进展中起关键作用。然而，在原子水平上RGD结构（环状或线性）与整合素αvβ3的相互作用影响仍知之甚少。在此，我们通过导向分子动力学模拟对整合素αvβ3与线性或环状五肽复合物进行了结合和解离动力学模拟。与环状RGD相比，线性RGD肽引发构型变化的不稳定性，主要是由于其灵活性而在于RGD结构域。通过良好的屏蔽以减少自由水分子的攻击，Mg²⁺与环状RGD之间的主要相互作用能比线性RGD系统强得多。力依赖性解离结果表明，线性RGD肽更容易离开活性位点，并且比环状RGD配体快得多，而线性RGD更难进入合适的活性结合位点。Ser123 - AspRGD键可能在变构途径中起关键作用。我们的发现为αvβ3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。
The 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.
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影响因子：
4.7
作者：
Liu S
通讯作者：
Liu S
DOI：
10.1034/j.1399-3011.1999.00052.x
发表时间：
1999-05-01
期刊：
JOURNAL OF PEPTIDE RESEARCH
影响因子：
--
作者：
Bogdanowich-Knipp, SJ;Chakrabarti, S;Siahaan, TJ
通讯作者：
Siahaan, TJ
影响因子：
5.4
作者：
Durrant JD;McCammon JA
通讯作者：
McCammon JA
影响因子：
5.7
作者：
Craig, D;Gao, M;Vogel, V
通讯作者：
Vogel, V
影响因子：
64.5
作者：
Takagi, J;Petre, BM;Springer, TA
通讯作者：
Springer, TA