Derivation and testing of pair potentials for protein folding. When is the quasichemical approximation correct?
Derivation and testing of pair potentials for protein folding. When is the quasichemical approximation correct?
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DOI：
10.1002/pro.5560060317
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发表时间：
1997-03
期刊：
影响因子：
8
通讯作者：
J. Skolnick;A. Godzik;L. Jaroszewski;12Andrzej Kolinski
中科院分区：
文献类型：
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作者：
J. Skolnick;A. Godzik;L. Jaroszewski;12Andrzej Kolinski
在没有氨基酸对特异性相互作用的情况下，许多现有的基于知识的统计偶势推导调用准化学近似来估计预期的侧链接触频率。乍一看，准化学近似认为蛋白质中的残基是断开的，并表示侧链接触概率与对残基的摩尔分数的乘积成正比，这似乎是相当严重的。为了研究这种近似的有效性，我们引入了两种新的参考状态，其中不允许氨基酸之间的特定对相互作用，但保留了蛋白质链的连通性。首先，通过将蛋白质作为高斯无序线圈聚合物来估计预期的侧链接触数。第二种，更现实的参考状态包括链连性、二级结构和链紧度的影响，通过将感兴趣的序列放置在与原始构象具有相似紧度的结构库的每个成员中来估计预期的侧链接触概率。侧链接触映射不允许重新调整到感兴趣的序列，即侧链不能重新打包。如果所有的氨基酸都是相同的大小，这种情况就会严格成立。这两种参考状态都有效地允许将侧链接触概率分解为序列相关项和结构相关项。然后，由于蛋白质中氨基酸的序列分布是随机的，这些参考状态的准化学近似被证明是很好的。因此，准化学近似的有效性范围取决于侧链重新包装项的大小，这是目前未知的。最后，通过不考虑间隙和考虑间隙的反折叠测试，评估了这两组对相互作用势以及基于侧链接触分数的相互作用量表的性能。
Many existing derivations of knowledge‐based statistical pair potentials invoke the quasichemical approximation to estimate the expected side‐chain contact frequency if there were no amino acid pair‐specific interactions. At first glance, the quasichemical approximation that treats the residues in a protein as being disconnected and expresses the side‐chain contact probability as being proportional to the product of the mole fractions of the pair of residues would appear to be rather severe. To investigate the validity of this approximation, we introduce two new reference states in which no specific pair interactions between amino acids are allowed, but in which the connectivity of the protein chain is retained. The first estimates the expected number of side‐chain contacts by treating the protein as a Gaussian random coil polymer. The second, more realistic reference state includes the effects of chain connectivity, secondary structure, and chain compactness by estimating the expected side‐chain contact probability by placing the sequence of interest in each member of a library of structures of comparable compactness to the native conformation. The side‐chain contact maps are not allowed to readjust to the sequence of interest, i.e., the side chains cannot repack. This situation would hold rigorously if all amino acids were the same size. Both reference states effectively permit the factorization of the side‐chain contact probability into sequence‐dependent and structure‐dependent terms. Then, because the sequence distribution of amino acids in proteins is random, the quasichemical approximation to each of these reference states is shown to be excellent. Thus, the range of validity of the quasichemical approximation is determined by the magnitude of the side‐chain repacking term, which is, at present, unknown. Finally, the performance of these two sets of pair interaction potentials as well as side‐chain contact fraction‐based interaction scales is assessed by inverse folding tests both without and with allowing for gaps.