Unraveling the Molecular Structure of the Catalytic Domain of Matrix Metalloproteinase-2 in Complex with a Triple-Helical Peptide by Means of Molecular Dynamics Simulations
Unraveling the Molecular Structure of the Catalytic Domain of Matrix Metalloproteinase-2 in Complex with a Triple-Helical Peptide by Means of Molecular Dynamics Simulations
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DOI：
10.1021/bi401144p
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发表时间：
2013-11-26
期刊：
影响因子：
2.9
通讯作者：
Valdes, Haydee
中科院分区：
文献类型：
--
作者：
Diaz, Natalia;Suarez, Dimas;Valdes, Haydee
在此，我们提出了一个计算研究的结果，采用各种模拟方法来建立和验证一系列的合成三螺旋肽（fTHP-5）的分子模型，无论是在其天然状态，并在一个prereactive复杂的MMP-2酶的催化结构域。首先，通过分子动力学（MD）模拟研究fTHP-5衬底的结构和动力学性质。然后，通过进行平均力计算的势来评估fTHP-5中的三条肽链中的每一条在易断裂的肽键周围扭曲的倾向。随后，fTHP-5的扭曲的几何形状在MMP-2活性位点内对接，遵循半刚性方案，并且最稳定的对接结构完全松弛，并且其特征在于在显式溶剂中通过广泛的MD模拟。遵循类似的方法，我们还研究了两个MMP-2催化单元和单个fTHP-5分子之间形成的假设三元复合物。总的来说，我们的MMP-2/fTHP-5复合物模型揭示了三螺旋扭曲的程度，以允许在MMP活性位点内容纳单个肽链。
Herein, we present the results of a computational study that employed various simulation methodologies to build and validate a series of molecular models of a synthetic triple-helical peptide (fTHP-5) both in its native state and in a prereactive complex with the catalytic domain of the MMP-2 enzyme. First, the structure and dynamical properties of the fTHP-5 substrate are investigated by means of molecular dynamics (MD) simulations. Then, the propensity of each of the three peptide chains in fTHP-5 to be distorted around the scissile peptide bond is assessed by carrying out potential of mean force calculations. Subsequently, the distorted geometries of fTHP-5 are docked within the MMP-2 active site following a semirigid protocol, and the most stable docked structures are fully relaxed and characterized by extensive MD simulations in explicit solvent. Following a similar approach, we also investigate a hypothetical ternary complex formed between two MMP-2 catalytic units and a single fTHP-5 molecule. Overall, our models for the MMP-2/fTHP-5 complexes unveil the extent to which the triple helix is distorted to allow the accommodation of an individual peptide chain within the MMP active site.