The Physical Basis for pH Sensitivity in Biomolecular Structure and Function, With Application to the Spike Protein of SARS-CoV-2.
The Physical Basis for pH Sensitivity in Biomolecular Structure and Function, With Application to the Spike Protein of SARS-CoV-2.
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DOI：
10.3389/fmolb.2022.834011
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发表时间：
2022
影响因子：
5
通讯作者：
Warwicker J
中科院分区：
文献类型：
--
作者：
Warwicker J
由于pH敏感性在生物学中具有基础性作用，因此已经致力于建立物理模型以合理化和预测来自分子结构的pH依赖性。两个关键的挑战是准确地计算可电离基团的溶剂化和水合作用，然后将这种建模应用于与所讨论的过程相关的所有构象。显式溶剂方法结合分子动力学模拟越来越多地补充低分辨率隐式溶剂技术，但同样，生物数据采集的规模留下了高通量建模的作用。此外，确定系统的结构范围允许对溶剂化中的关键阶段进行采样。在该领域的审查，它强调，pH传感器在生物学以外的最明显的候选人（组氨酸侧链，在接近中性的pH下具有未改变的pK）;建模可以受益于生物信息学中的其他概念，特别是同源物家族中的相互作用和功能的调节;并且，结合尽可能多的实验结构也是有益的，以减轻构象中的小变化并分析更大的功能性构象变化。这些方面，然后证明了与新的工作对穗蛋白的SARS-CoV-2，在pH值的依赖性的变体，包括预测的变化在平衡的锁定，封闭，和开放的形式在中性pH值的Omicron变体穗蛋白。
Since pH sensitivity has a fundamental role in biology, much effort has been committed to establishing physical models to rationalize and predict pH dependence from molecular structures. Two of the key challenges are to accurately calculate ionizable group solvation and hydration and then to apply this modeling to all conformations relevant to the process in question. Explicit solvent methods coupled to molecular dynamics simulation are increasingly complementing lower resolution implicit solvent techniques, but equally, the scale of biological data acquisition leaves a role for high-throughput modeling. Additionally, determination of ranges of structures for a system allows sampling of key stages in solvation. In a review of the area, it is emphasized that pH sensors in biology beyond the most obvious candidate (histidine side chain, with an unshifted pK a near neutral pH) should be considered; that modeling can benefit from other concepts in bioinformatics, in particular modulation of interactions and function in families of homologs; and that it can also be beneficial to incorporate as many experimental structures as possible, to mitigate against small variations in conformation and to analyze larger, functional, conformational changes. These aspects are then demonstrated with new work on the spike protein of SARS-CoV-2, looking at the pH dependence of variants, including prediction of a change in the balance of locked, closed, and open forms at neutral pH for the Omicron variant spike protein.
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影响因子：
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作者：
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