Localizing Frustration in Proteins Using All-Atom Energy Functions
Localizing Frustration in Proteins Using All-Atom Energy Functions
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DOI：
10.1021/acs.jpcb.9b01545
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发表时间：
2019-05-30
影响因子：
3.3
通讯作者：
Clementi, Cecilia
中科院分区：
文献类型：
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作者：
Chen, Justin;Schafer, Nicholas P.;Clementi, Cecilia
蛋白质折叠和蛋白质设计的问题是同一枚硬币的两面。蛋白质折叠涉及在给定固定序列的情况下探索蛋白质的构型空间，而蛋白质设计涉及在给定特定目标结构的情况下在序列空间中搜索。为了使蛋白质快速可靠地折叠，其能量景观必须在其整个构型空间中偏向折叠的集合体，并且必须缺乏深的动力学陷阱，否则会阻碍折叠。进化已经“设计”了许多天然蛋白质的序列，通过漫长的随机突变和选择过程，以最小程度的挫折产生景观。希望设计出折叠成特定结构的蛋白质序列的人类面临的任务是使用可用的近似能量函数来塑造实验室中工作的漏斗状景观。在这项工作中，我们演示了如何使用全原子能量函数计算几个本地化的挫折措施。具体来说，我们采用了Rosetta能量函数，该函数已成功用于设计蛋白质，并且具有适当溶剂平均的自然成对分解。我们计算了突变的WW结构域FiP35和完全由人类设计的三螺旋束Alpha3D的这些新开发的挫折措施。FiP35的结构表现出比Alpha3D更少的局部挫折。FiP35中WW结构域的共有序列的突变（其在实验中已出乎意料地显示破坏折叠）通过破坏疏水核心而诱导局部挫折。通过对Alpha3D序列进行有限的重新设计，我们发现一些（但不是全部）降低能量的突变也会导致挫折感减少。结果表明，除了用于检测蛋白质结构中的残余挫折之外，优化这里提出的局部挫折措施可能是平衡蛋白质设计任务中的正面和负面设计的有用和自动的手段。
The problems of protein folding and protein design are two sides of the same coin. Protein folding involves exploring a protein's configuration space given a fixed sequence, whereas protein design involves searching in sequence space given a particular target structure. For a protein to fold quickly and reliably, its energy landscape must be biased toward the folded ensemble throughout its configuration space and must lack deep kinetic traps that would otherwise frustrate folding. Evolution has "designed" the sequences of many naturally occurring proteins, through an eons-long process of random mutation and selection, to yield landscapes with a minimal degree of frustration. The task facing humans hoping to design protein sequences that fold into particular structures is to use the available approximate energy functions to sculpt funneled landscapes that work in the laboratory. In this work, we demonstrate how to calculate several localized frustration measures using an all-atom energy function. Specifically, we employ the Rosetta energy function, which has been used successfully to design proteins and which has a natural pairwise decomposition that is suitably solvent-averaged. We calculate these newly developed frustration measures for both a mutated WW domain, FiP35, and a three-helix bundle that was designed completely by humans, Alpha3D. The structure of FiP35 exhibits less localized frustration than that of Alpha3D. A mutation toward the consensus sequence for WW domains in FiP35, which has been shown unexpectedly in experiment to disrupt folding, induces localized frustration by disrupting the hydrophobic core. By performing a limited redesign on the sequence of Alpha3D, we show that some, but not all, mutations that lower the energy also result in decreased frustration. The results suggest that, in addition to being useful for detecting residual frustration in protein structures, optimizing the localized frustration measures presented here may be a useful and automatic means of balancing positive and negative design in protein design tasks.