Shortle D, Simons K T, Baker D
Department of Biochemistry, University of Washington School of Medicine, Seattle, WA 98195, USA.
Proc Natl Acad Sci U S A. 1998 Sep 15;95(19):11158-62. doi: 10.1073/pnas.95.19.11158.
Recent experimental studies of the denatured state and theoretical analyses of the folding landscape suggest that there are a large multiplicity of low-energy, partially folded conformations near the native state. In this report, we describe a strategy for predicting protein structure based on the working hypothesis that there are a greater number of low-energy conformations surrounding the correct fold than there are surrounding low-energy incorrect folds. To test this idea, 12 ensembles of 500 to 1,000 low-energy structures for 10 small proteins were analyzed by calculating the rms deviation of the Calpha coordinates between each conformation and every other conformation in the ensemble. In all 12 cases, the conformation with the greatest number of conformations within 4-A rms deviation was closer to the native structure than were the majority of conformations in the ensemble, and in most cases it was among the closest 1 to 5%. These results suggest that, to fold efficiently and retain robustness to changes in amino acid sequence, proteins may have evolved a native structure situated within a broad basin of low-energy conformations, a feature which could facilitate the prediction of protein structure at low resolution.
近期关于变性状态的实验研究以及折叠景观的理论分析表明，在天然状态附近存在大量低能量、部分折叠的构象。在本报告中，我们描述了一种基于工作假设预测蛋白质结构的策略，该假设认为围绕正确折叠的低能量构象数量比围绕低能量错误折叠的构象数量更多。为了验证这一想法，通过计算每个构象与集合中其他每个构象之间Cα坐标的均方根偏差，对10个小蛋白质的12个包含500至1000个低能量结构的集合进行了分析。在所有12种情况下，均方根偏差在4埃以内的构象数量最多的构象比集合中的大多数构象更接近天然结构，并且在大多数情况下，它处于最接近的1%至5%之中。这些结果表明，为了高效折叠并保持对氨基酸序列变化的稳健性，蛋白质可能已经进化出一种位于广泛低能量构象盆地内的天然结构，这一特征可能有助于低分辨率下蛋白质结构的预测。
