Biophysical Journal:利用最低能量值法探索分子对接
在一定程度上，由于与药物计算机辅助设计相关，分子对接成为热门的研究领域。早期的方法主要关注使用刚性的配体与刚性的受体的对接作用，伴随着高性能计算机科技的快速发展和新的对接算法方面的进展，在对接效应中将配体和其相应受体当作结构灵活的分子来研究已经成为可能。
美国密苏里大学圣路易斯分校的Wong等研究人员利用已为人所熟知的大分子蛋白质-配体系统的复杂能量地貌法，采用模拟退火作为工具来寻找最低能量点。研究中，将此法应用于磷-硫酸硝基邻苯二酚与耶尔森氏菌属蛋白质酪氨酸磷酸酶的对接作用。细菌的酪氨酸磷酸酶可导致从肠胃病症到黑死病等人类疾病。通过模拟显示，在连接口处有三种不同的对接形态，其中一种为正确的对接结构，另外两种则为错误的对接结构。此外，他们还观测到从所研究的蛋白质表面到正确的对接路径的四种对接途径。具有最低能量结构的联接束质心的晶体结构平方根标准差仅为0.67?（1?=10-10m）。此结构显然比单单使用结合能的方法所得到1.66? 要更精确。研究显示pNCS的硫酸根基团对于连接和指导对接过程中配体靶向联结位置中承担重要角色。蛋白质的结构灵活度也对辅助配体进入抑或离开连接口有着重要的意义。
相关论文发表在《生物物理学杂志》（Biophysical Journal）上。（科学新闻杂志 徐磊/编译）
生物谷推荐原始出处：
（Biophysical Journal），93:4141-4150 (2007)，Zunnan Huang，Chung F. Wong
A Mining Minima Approach to Exploring the Docking Pathways of p-Nitrocatechol Sulfate to YopH
Zunnan Huang and Chung F. Wong
Using the docking of p-nitrocatechol sulfate to Yersinia protein tyrosine phosphatase YopH as an example, we showed that an approach based on mining minima followed by cluster and similarity analysis could generate useful insights into docking pathways. Our simulation treated both the ligand and the protein as flexible molecules so that the coupling between their motion could be properly accounted for. Our simulation identified three docking poses; the one with the lowest energy agreed well with experimental structure. The model also predicted the side-chain conformations of the amino acids lying in the binding pocket correctly with the exception of three residues that appeared to be stabilized by two structural water molecules in the crystal structure. The implicit solvent model employed in the simulation could not capture such effects well. We also found four major pathways leading to these docking poses after the ligand entered the mouth of the binding pocket. In addition, the sulfate group of p-nitrocatechol sulfate was found to be important both in binding the ligand to the pocket and in guiding the ligand to dock into the pocket. The coupling of the motion between the protein and the ligand also played an important role in facilitating ligand loading and unloading.
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