Knowledge-based potential defined for a rotamer library to design protein sequences.
Knowledge-based potential defined for a rotamer library to design protein sequences.
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DOI：
10.1093/protein/14.8.557
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发表时间：
2001-08
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影响因子：
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通讯作者：
Motonori Ota;Yasuhiro Isogai;Ken Nishikawa
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文献类型：
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作者：
Motonori Ota;Yasuhiro Isogai;Ken Nishikawa
开发了旋转异构体库的基于知识的潜力来设计蛋白质序列。蛋白质侧链构象由 56 个模板表示。它们对给定结构场地环境的适应性是通过三个基于知识的术语（即二体侧链堆积、一体水合和局部构象）的组合函数来评估的。预先计算的天然序列与数据库中的结构位点环境之间的匹配数以及实际解决的错配数被转化为能量得分。在best-14测试（评估56个适应度排名位置的四分之一内天然旋转异构体在其结构位点上的繁殖能力）、对人和T4溶菌酶突变体的结构稳定性分析以及针对序列数据库的结构图谱的反向折叠搜索中，该函数的表现优于传统归一化推导的函数和我们之前开发的函数。针对各种结构基序，对该功能进行从头序列设计。由此获得的序列表现出合理的分子量和与目标的天然序列相似的疏水/亲水模式，并且在 BLASTP 搜索中就像它们是目标蛋白的同源物一样。我们从归一化的参考状态和短程排斥对防止残留碰撞的关键作用方面讨论了这一显着改进。
A knowledge-based potential for a rotamer library was developed to design protein sequences. Protein side-chain conformations are represented by 56 templates. Each of their fitness to a given structural site-environment is evaluated by a combined function of the three knowledge-based terms, i.e. two-body side-chain packing, one-body hydration and local conformation. The number of matches between the native sequence and the structural site-environment in the database and that of the virtually settled mismatches, counted in advance, were transformed into the energy scores. In the best-14 test (assessment for the reproduction ability of the native rotamer on its structural site within a quarter of 56 fitness rank positions), the structural stability analysis on mutants of human and T4 lysozymes and the inverse-folding search by a structure profile against the sequence database, this function performs better than the function deduced with the conventional normalization and our previously developed function. Targeting various structural motifs, de novo sequence design was conducted with the function. The sequences thus obtained exhibit reasonable molecular masses and hydrophobic/hydrophilic patterns similar to the native sequences of the target and act as if they were the homologs to the target proteins in BLASTP search. This significant improvement is discussed in terms of the reference state for normalization and the crucial role of short-range repulsion to prohibit residue bumps.