Simkovic Felix, Ovchinnikov Sergey, Baker David, Rigden Daniel J
Institute of Integrative Biology, University of Liverpool, Liverpool L69 7ZB, England.
Department of Biochemistry, University of Washington, Seattle, WA 98195, USA.
IUCrJ. 2017 Apr 18;4(Pt 3):291-300. doi: 10.1107/S2052252517005115. eCollection 2017 May 1.
Evolutionary pressure on residue interactions, intramolecular or intermolecular, that are important for protein structure or function can lead to covariance between the two positions. Recent methodological advances allow much more accurate contact predictions to be derived from this evolutionary covariance signal. The practical application of contact predictions has largely been confined to structural bioinformatics, yet, as this work seeks to demonstrate, the data can be of enormous value to the structural biologist working in X-ray crystallo-graphy, cryo-EM or NMR. Integrative structural bioinformatics packages such as can already exploit contact predictions in a variety of ways. The contribution of contact predictions begins at construct design, where structural domains may need to be expressed separately and contact predictions can help to predict domain limits. Structure solution by molecular replacement (MR) benefits from contact predictions in diverse ways: in difficult cases, more accurate search models can be constructed using modelling when predictions are available, while intermolecular contact predictions can allow the construction of larger, oligomeric search models. Furthermore, MR using supersecondary motifs or large-scale screens against the PDB can exploit information, such as the parallel or antiparallel nature of any β-strand pairing in the target, that can be inferred from contact predictions. Contact information will be particularly valuable in the determination of lower resolution structures by helping to assign sequence register. In large complexes, contact information may allow the identity of a protein responsible for a certain region of density to be determined and then assist in the orientation of an available model within that density. In NMR, predicted contacts can provide long-range information to extend the upper size limit of the technique in a manner analogous but complementary to experimental methods. Finally, predicted contacts can distinguish between biologically relevant interfaces and mere lattice contacts in a final crystal structure, and have potential in the identification of functionally important regions and in foreseeing the consequences of mutations.
对蛋白质结构或功能至关重要的残基相互作用（分子内或分子间）的进化压力可导致两个位置之间的共变。最近的方法学进展使得能够从这种进化共变信号中得出更准确的接触预测。接触预测的实际应用在很大程度上局限于结构生物信息学，然而，正如本研究试图证明的那样，这些数据对于从事X射线晶体学、冷冻电镜或核磁共振研究的结构生物学家可能具有巨大价值。诸如 这样的综合结构生物信息学软件包已经能够以多种方式利用接触预测。接触预测的作用始于构建体设计，此时可能需要分别表达结构域，而接触预测有助于预测结构域边界。通过分子置换（MR）进行结构解析以多种方式受益于接触预测：在困难的情况下，当有预测可用时，可以使用 建模构建更准确的搜索模型，而分子间接触预测可以构建更大的寡聚体搜索模型。此外，使用超二级基序或针对蛋白质数据库进行大规模筛选的MR可以利用从接触预测中推断出的信息，例如目标中任何β链配对的平行或反平行性质。接触信息在通过帮助确定序列比对来确定低分辨率结构时将特别有价值。在大型复合物中，接触信息可以确定负责特定密度区域的蛋白质的身份，然后协助在该密度内确定可用模型的方向。在核磁共振中，预测的接触可以提供远程信息，以类似于但补充实验方法的方式扩展该技术的尺寸上限。最后，预测的接触可以区分最终晶体结构中的生物学相关界面和仅仅是晶格接触，并在识别功能重要区域和预测突变后果方面具有潜力。
