Gin Brian C, Garrahan Juan P, Geissler Phillip L
Department of Chemistry, University of California at Berkeley, Berkeley, CA 94720, USA.
J Mol Biol. 2009 Oct 9;392(5):1303-14. doi: 10.1016/j.jmb.2009.06.058. Epub 2009 Jul 2.
Models of protein energetics that neglect interactions between amino acids that are not adjacent in the native state, such as the Gō model, encode or underlie many influential ideas on protein folding. Implicit in this simplification is a crucial assumption that has never been critically evaluated in a broad context: Detailed mechanisms of protein folding are not biased by nonnative contacts, typically argued to be a consequence of sequence design and/or topology. Here we present, using computer simulations of a well-studied lattice heteropolymer model, the first systematic test of this oft-assumed correspondence over the statistically significant range of hundreds of thousands of amino acid sequences that fold to the same native structure. Contrary to previous conjectures, we find a multiplicity of folding mechanisms, suggesting that Gō-like models cannot be justified by considerations of topology alone. Instead, we find that the crucial factor in discriminating among topological pathways is the heterogeneity of native contact energies: The order in which native contacts accumulate is profoundly insensitive to omission of nonnative interactions, provided that native contact heterogeneity is retained. This robustness holds over a surprisingly wide range of folding rates for our designed sequences. Mirroring predictions based on the principle of minimum frustration, fast-folding sequences match their Gō-like counterparts in both topological mechanism and transit times. Less optimized sequences dwell much longer in the unfolded state and/or off-pathway intermediates than do Gō-like models. For dynamics that bridge unfolded and unfolded states, however, even slow folders exhibit topological mechanisms and transit times nearly identical with those of their Gō-like counterparts. Our results do not imply a direct correspondence between folding trajectories of Gō-like models and those of real proteins, but they do help to clarify key topological and energetic assumptions that are commonly used to justify such caricatures.
诸如Gō模型这类忽略天然状态下不相邻氨基酸之间相互作用的蛋白质能量学模型，编码了许多关于蛋白质折叠的有影响力的观点，或者是这些观点的基础。这种简化隐含着一个关键假设，而这个假设从未在广泛的背景下得到严格评估：蛋白质折叠的详细机制不会受到非天然接触的影响，通常认为这是序列设计和/或拓扑结构的结果。在这里，我们使用一个经过充分研究的晶格杂聚物模型进行计算机模拟，首次在数十万折叠成相同天然结构的氨基酸序列的统计学显著范围内，对这个经常被假设的对应关系进行了系统测试。与之前的推测相反，我们发现了多种折叠机制，这表明仅考虑拓扑结构并不能证明类似Gō的模型是合理的。相反，我们发现区分拓扑路径的关键因素是天然接触能量的异质性：只要保留天然接触的异质性，天然接触积累的顺序对非天然相互作用的忽略就非常不敏感。对于我们设计的序列，这种稳健性在令人惊讶的广泛折叠速率范围内都成立。基于最小受挫原则的预测反映出，快速折叠序列在拓扑机制和过渡时间上与类似Gō的对应序列相匹配。优化程度较低的序列在未折叠状态和/或偏离路径的中间体中停留的时间比类似Gō的模型长得多。然而，对于连接未折叠状态和未折叠状态的动力学，即使是折叠缓慢的序列也表现出与类似Gō的对应序列几乎相同的拓扑机制和过渡时间。我们的结果并不意味着类似Gō的模型的折叠轨迹与真实蛋白质的折叠轨迹之间存在直接对应关系，但它们确实有助于阐明通常用于证明此类简化模型合理性的关键拓扑和能量假设。
