Mirny L A, Shakhnovich E I
Department of Chemistry and Chemical Biology, Harvard University, 12 Oxford Street, Cambridge, MA, 02138, USA.
J Mol Biol. 1998 Oct 23;283(2):507-26. doi: 10.1006/jmbi.1998.2092.
We developed a novel Monte Carlo threading algorithm which allows gaps and insertions both in the template structure and threaded sequence. The algorithm is able to find the optimal sequence-structure alignment and sample suboptimal alignments. Using our algorithm we performed sequence-structure alignments for a number of examples for three protein folds (ubiquitin, immunoglobulin and globin) using both "ideal" set of potentials (optimized to provide the best Z-score for a given protein) and more realistic knowledge-based potentials. Two physically different scenarios emerged. If a template structure is similar to the native one (within 2 A RMS), then (i) the optimal threading alignment is correct and robust with respect to deviations of the potential from the "ideal" one; (ii) suboptimal alignments are very similar to the optimal one; (iii) as Monte Carlo temperature decreases a sharp cooperative transition to the optimal alignment is observed. In contrast, if the template structure is only moderately close to the native structure (RMS greater than 3.5 A), then (i) the optimal alignment changes dramatically when an "ideal" potential is substituted by the real one; (ii) the structures of suboptimal alignments are very different from the optimal one, reducing the reliability of the alignment; (iii) the transition to the apparently optimal alignment is non-cooperative. In the intermediate cases when the RMS between the template and the native conformations is in the range between 2 A and 3.5 A, the success of threading alignment may depend on the quality of potentials used. These results are rationalized in terms of a threading free energy landscape. Possible ways to overcome the fundamental limitations of threading are discussed briefly.
我们开发了一种新颖的蒙特卡罗穿线算法，该算法允许模板结构和穿线序列中都存在空位和插入。该算法能够找到最优的序列-结构比对，并对次优比对进行抽样。我们使用该算法，针对三种蛋白质折叠（泛素、免疫球蛋白和珠蛋白）的多个示例，使用“理想”的势集（针对给定蛋白质进行优化以提供最佳Z值）和更符合实际的基于知识的势进行了序列-结构比对。出现了两种物理上不同的情况。如果模板结构与天然结构相似（均方根偏差在2埃以内），那么：（i）最优穿线比对对于势偏离“理想”势的情况是正确且稳健的；（ii）次优比对与最优比对非常相似；（iii）随着蒙特卡罗温度降低，会观察到向最优比对的急剧协同转变。相反，如果模板结构仅适度接近天然结构（均方根偏差大于3.5埃），那么：（i）当用实际势替代“理想”势时，最优比对会发生显著变化；（ii）次优比对的结构与最优比对非常不同，降低了比对的可靠性；（iii）向明显最优比对的转变是非协同的。在模板与天然构象之间的均方根偏差处于2埃至3.5埃范围内的中间情况下，穿线比对的成功可能取决于所使用势的质量。这些结果根据穿线自由能景观得到了合理的解释。简要讨论了克服穿线基本局限性的可能方法。
