Department of Chemistry & Biochemistry, South Dakota State University, Brookings, South Dakota, USA.
Protein Sci. 2023 Oct;32(10):e4762. doi: 10.1002/pro.4762.
Weak molecular interactions play an important role in protein structure and function. Computational tools that identify weak molecular interactions are, therefore, valuable for the study of proteins. Here, we present AQcalc, a web server (https://aqcalcbiocomputing.com/) that can be used to identify anion-quadrupole (AQ) interactions, which are weak interactions involving aromatic residue (Trp, Tyr, and Phe) ring edges and anions (Asp, Glu, and phosphate ion) both within proteins and at their interfaces (protein-protein, protein-nucleic acids, and protein-lipid bilayer). AQcalc identifies AQ interactions as well as clusters involving AQ, cation-π, and salt bridges, among others. Utilizing AQcalc we analyzed weak interactions in protein models, even in the absence of experimental structures, to understand the contributions of weak interactions to deleterious structural changes, including those associated with oncogenic and germline disease variants. We identified several deleterious variants with disrupted AQ interactions (comparable in frequency to cation-π disruptions). Amyloid fibrils utilize AQ to bury anions at frequencies that far exceed those observed for globular proteins. AQ interactions were detected three and five times more frequently than the hydrogen-bonded AQ (HBAQ) in fibril structures and protein-lipid bilayer interfaces, respectively. By contrast, AQ and HBAQ interactions were detected with similar frequencies in globular proteins. Collectively, these findings suggest AQcalc will be effective in facilitating fine structural analysis. As other web utilities designed to identify protein residue interaction networks do not report AQ interactions, wide use of AQcalc will enrich our understanding of residue interaction networks and facilitate hypothesis testing by identifying and experimentally characterizing these comparably weak but important interactions.
弱分子相互作用在蛋白质结构和功能中起着重要作用。因此，能够识别弱分子相互作用的计算工具对于蛋白质研究非常有价值。在这里，我们介绍了 AQcalc，这是一个可以用于识别阴离子-偶极（AQ）相互作用的网络服务器（https://aqcalcbiocomputing.com/），这些相互作用涉及芳香残基（Trp、Tyr 和 Phe）环边缘和阴离子（Asp、Glu 和磷酸离子），无论是在蛋白质内部还是在它们的界面（蛋白质-蛋白质、蛋白质-核酸和蛋白质-脂质双层）中。AQcalc 可以识别 AQ 相互作用以及涉及 AQ、阳离子-π 和盐桥等的簇。利用 AQcalc，我们分析了蛋白质模型中的弱相互作用，即使在没有实验结构的情况下，也可以了解弱相互作用对有害结构变化的贡献，包括与致癌和种系疾病变体相关的变化。我们发现了几种具有破坏 AQ 相互作用的有害变体（与阳离子-π 破坏的频率相当）。淀粉样纤维利用 AQ 以远远超过球状蛋白的频率将阴离子埋藏起来。在纤维结构和蛋白质-脂质双层界面中，AQ 相互作用的检测频率分别比氢键结合的 AQ（HBAQ）高出三到五倍。相比之下，在球状蛋白中，AQ 和 HBAQ 相互作用的检测频率相似。总的来说，这些发现表明 AQcalc 将有效地促进精细结构分析。由于其他旨在识别蛋白质残基相互作用网络的网络工具不报告 AQ 相互作用，因此广泛使用 AQcalc 将丰富我们对残基相互作用网络的理解，并通过识别和实验表征这些相对较弱但重要的相互作用来促进假设检验。
