论文标题
通过与共同进化势相互作用的粗粒模型研究的钙粘着蛋白之间的分子识别
Molecular recognition between cadherins studied by a coarse-grained model interacting with a coevolutionary potential
论文作者
论文摘要
研究钙粘蛋白二聚化涉及的构象与了解组织及其衰竭的发展高度相关，这与肿瘤和转移有关。实验技术，例如X射线晶体学，通常只能报告最稳定的构象，而缺失的少数族裔仍然可能对识别机制很重要。计算机模拟可能是实验方法的有效补充。但是，在显式溶剂中，标准的全原子蛋白模型在计算上太要求了，无法彻底搜索由数百种氨基酸组成的多个链的构象空间。为了实现这一目标，我们以隐式溶剂为基础的粗粒模型。这种模型的标准问题是找到描述其相互作用的现实潜力。我们使用了通过统计潜力校正的钙粘蛋白比对的协同进化信息，以建立蛋白质实验构象不可知的相互作用电位。使用此模型，我们探索了多链系统的构象空间，并验证了与实验数据相比的结果。我们确定了序列特异性的二聚体构象，这对于合理化钙粘蛋白之间的识别机理可能是有用的。
Studying the conformations involved in the dimerization of cadherins is highly relevant to understand the development of tissue and its failure, which is associated with tumors and metastases. Experimental techniques, like X-ray crystallography, can usually report only the most stable conformations, missing minority states that could nonetheless be important for the recognition mechanism. Computer simulations could be a valid complement to the experimental approach. However, standard all-atom protein models in explicit solvent are computationally too demanding to search thoroughly the conformational space of multiple chains composed of several hundreds of amino acids. To reach this goal, we resorted to a coarse-grained model in implicit solvent. The standard problem with this kind of models is to find a realistic potential to describe their interactions. We used coevolutionary information from cadherin alignments, corrected by a statistical potential, to build an interaction potential which is agnostic of the experimental conformations of the protein. Using this model, we explored the conformational space of multi-chain systems and validated the results comparing with experimental data. We identified dimeric conformations that are sequence-specific and that can be useful to rationalize the mechanism of recognition between cadherins.
