Molecular docking and analysis of interactions between vascular endothelial growth factor (VEGF) and SPARC protein
Molecular docking and analysis of interactions between vascular endothelial growth factor (VEGF) and SPARC protein
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DOI：
10.1016/j.jmgm.2007.05.001
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发表时间：
2007-11-01
影响因子：
2.9
通讯作者：
Taylor, Ethan Will
中科院分区：
文献类型：
--
作者：
Chandrasekaran, Vasu;Ambati, Jayakrishna;Taylor, Ethan Will
骨连接素/骨连接素的细胞外模块与血管内皮生长因子（VEGF）结合并抑制VEGF刺激的内皮细胞增殖。在试图确定VEGF上的结合位点时，我们假设该结合位点可能至少部分地与VEGF受体I（VEGFR-1）的结合位点重叠，因为VEGF通过阻止VEGF诱导的VEGFR-1磷酸化而起作用。为此，使用预测对接工具进行对接模拟，以获得VEGF-血管内皮细胞复合物的模型结构。VEGF-VEGF复合物的预测结构表明VEGF的胞外结构域与VEGF的VEGFR-I结合位点相互作用，并且与已知的生化数据一致。分子动力学细化后，在蛋白质界面的侧链相互作用被确定为预测大大有助于结合的自由能。这些提供了蛋白质-蛋白质界面处的关键氨基酸侧链相互作用的详细预测。为了进一步验证模型，将使用鉴定的相互作用设计诱变研究，以研究其对结合活性的影响。该模型的VEGF-血管生成素复合物应提供一个基础，为未来的研究，旨在确定抑制剂的VEGF诱导的血管生成。(c)2007爱思唯尔公司All rights reserved.
The extracellular module of SPARC/osteonectin binds to vascular endothelial growth factor (VEGF) and inhibits VEGF-stimulated proliferation of endothelial cells. In an attempt to identify the binding site for SPARC on VEGF, we hypothesized that this binding site could overlap at least partially the binding site of VEGF receptor I (VEGFR-1), as SPARC acts by preventing VEGF-induced phosphorylation of VEGFR-1. To this end, a docking simulation was carried out using a predictive docking tool to obtain modeled structures of the VEGF-SPARC complex. The predicted structure of VEGF-SPARC complex indicates that the extracellular domain of SPARC interacts with the VEGFR-I binding site of VEGF, and is consistent with known biochemical data. Following molecular dynamics refinement, side-chain interactions at the protein interface were identified that were predicted to contribute substantially to the free energy of binding. These provide a detailed prediction of key amino acid side-chain interactions at the protein-protein interface. To validate the model further, the identified interactions will be used for designing mutagenesis studies to investigate their effect on binding activity. This model of the VEGF-SPARC complex should provide a basis for future studies aimed at identifying inhibitors of VEGF-induced angiogenesis. (c) 2007 Elsevier Inc. All rights reserved.