Using a hydrophobic contact potential to evaluate native and near-native folds generated by molecular dynamics simulations
Using a hydrophobic contact potential to evaluate native and near-native folds generated by molecular dynamics simulations
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DOI：
10.1006/jmbi.1996.0196
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发表时间：
1996-04-05
影响因子：
5.6
通讯作者：
Levitt, M
中科院分区：
文献类型：
--
作者：
Huang, ES;Subbiah, S;Levitt, M
对于给定的氨基酸序列，有几种基于知识的能量函数可以区分天然折叠和严重错误折叠的诱饵库。这些诱饵通常是通过将序列安装或“穿线”到不相关蛋白质结构的主链上而生成的，往往不紧凑，并且与天然结构有很大不同：与天然结构的均方根 (RMS) 偏差通常在 15 至 20 埃的范围内。当呈现与正确结构构象仅略有不同的紧凑诱饵时（即 RMS 偏差类似于 5 埃或更小的诱饵），有效的能量函数也应表现出类似的识别能力。最近，我们基于天然折叠形成疏水核心的趋势，开发了一种简单而强大的天然折叠识别方法。我们的能量测量（我们称之为疏水适应性评分）面临的挑战是从为 5 个小单体蛋白中的每一个生成的 2000 个近天然结构中识别天然折叠。首先，在室温下通过分子动力学模拟生成每种蛋白质的 1000 个构象。这组 5000 个的平均 RMS 偏差为 1.5 埃。总共有 323 个诱饵的能量低于原生诱饵；然而，这些的 RMS 偏差均不大于 2 埃。每个在高温下又生成了 1000 个结构，其中探索了更大范围的构象空间（平均 RMS 偏差为 4.3 埃）。在这组诱饵中，只有七个诱饵被误识别。构象的疏水适应能强烈依赖于 RMS 偏差。平均而言，我们的潜力产生的能量值对于在室温下生成的结构群体来说是最低的，对于在高温下生成的结构来说是中间的，对于通过螺纹方法构建的结构来说是最高的。一般来说，最低能量的诱饵构象的主链非常接近天然结构。讨论了我们的方法用于筛选骨干候选物以通过侧链包装优化进行建模的可能用途。 (C) 1996 学术出版社有限公司
There are several knowledge-based energy functions that can distinguish the native fold from a pool of grossly misfolded decoys for a given sequence of amino acids. These decoys, which are typically generated by mounting, or ''threading'', the sequence onto the backbones of unrelated protein structures, tend to be non-compact and quite different from the native structure: the root-mean-squared (RMS) deviations fron the native are commonly in the range of 15 to 20 Angstrom. Effective energy functions should also demonstrate a similar recognition capability when presented with compact decoys that depart only slightly in conformation from the correct structure (i.e. those with RMS deviations of similar to 5 Angstrom or less). Recently, we developed a simple yet powerful method for native fold recognition based on the tendency for native folds to form hydrophobic cores. Our energy measure, which we call the hydrophobic fitness score, is challenged to recognize the native fold from 2000 near-native structures generated for each of five small monomeric proteins. First, 1000 conformations for each protein were generated by molecular dynamics simulation at room temperature. The average RMS deviation of this set of 5000 was 1.5 Angstrom. A total of 323 decoys had energies lower than native; however, none of these had RMS deviations greater than 2 Angstrom. Another 1000 structures were generated for each at high temperature, in which a greater range of conformational space was explored (4.3 Angstrom average RMS deviation). Out of this set, only seven decoys were misrecognized. The hydrophobic fitness energy of a conformation is strongly dependent upon the RMS deviation. On average our potential yields energy values which are lowest for the population of structures generated at room temperature, intermediate for those produced at high temperature and highest for those constructed by threading methods. In general, the lowest energy decoy conformations have backbones very close to native structure. The possible utility of our method for screening backbone candidates for the purpose of modelling by side-chain packing optimization is discussed. (C) 1996 Academic Press Limited