Fleming Patrick J, Gong Haipeng, Rose George D
TC Jenkins Department of Biophysics, Johns Hopkins University, Baltimore, Maryland 21218, USA.
Protein Sci. 2006 Aug;15(8):1829-34. doi: 10.1110/ps.062305106. Epub 2006 Jul 5.
Using a test set of 13 small, compact proteins, we demonstrate that a remarkably simple protocol can capture native topology from secondary structure information alone, in the absence of long-range interactions. It has been a long-standing open question whether such information is sufficient to determine a protein's fold. Indeed, even the far simpler problem of reconstructing the three-dimensional structure of a protein from its exact backbone torsion angles has remained a difficult challenge owing to the small, but cumulative, deviations from ideality in backbone planarity, which, if ignored, cause large errors in structure. As a familiar example, a small change in an elbow angle causes a large displacement at the end of your arm; the longer the arm, the larger the displacement. Here, correct secondary structure assignments (alpha-helix, beta-strand, beta-turn, polyproline II, coil) were used to constrain polypeptide backbone chains devoid of side chains, and the most stable folded conformations were determined, using Monte Carlo simulation. Just three terms were used to assess stability: molecular compaction, steric exclusion, and hydrogen bonding. For nine of the 13 proteins, this protocol restricts the main chain to a surprisingly small number of energetically favorable topologies, with the native one prominent among them.
我们使用一组包含13种小型紧密蛋白的测试集，证明了在不存在长程相互作用的情况下，一个非常简单的方案仅从二级结构信息就能捕捉到天然拓扑结构。这样的信息是否足以确定蛋白质的折叠一直是一个长期存在的开放性问题。事实上，即使是从精确的主链扭转角重建蛋白质三维结构这个简单得多的问题，由于主链平面性与理想情况存在微小但累积的偏差，如果忽略这些偏差，会导致结构出现大的误差，所以仍然是一项艰巨的挑战。举一个常见的例子，肘部角度的微小变化会导致手臂末端的大位移；手臂越长，位移越大。在这里，正确的二级结构分配（α-螺旋、β-链、β-转角、多聚脯氨酸II、无规卷曲）被用于约束没有侧链的多肽主链，并且使用蒙特卡罗模拟确定最稳定的折叠构象。仅使用了三个项来评估稳定性：分子紧密性、空间排斥和氢键。对于这13种蛋白质中的9种，该方案将主链限制在数量惊人少的能量有利拓扑结构中，其中天然拓扑结构最为突出。
