Department of Chemical Engineering, University of New Hampshire, Durham, New Hampshire 03824, United States.
J Chem Inf Model. 2023 Aug 14;63(15):4864-4874. doi: 10.1021/acs.jcim.3c00835. Epub 2023 Jul 24.
Riboswitches are conserved functional domains in mRNA that almost exclusively exist in bacteria. They regulate the biosynthesis and transport of amino acids and essential metabolites such as coenzymes, nucleobases, and their derivatives by specifically binding small molecules. Due to their ability to precisely discriminate between different cognate molecules as well as their common existence in bacteria, riboswitches have become potential antibacterial drug targets that could deliver urgently needed antibiotics with novel mechanisms of action. In this work, we report the recognition mechanisms of four oxidization products (XAN, AZA, UAC, and HPA) generated during purine degradation by an RNA motif termed the riboswitch. Specifically, we investigated the physical interactions between the riboswitch and the oxidized metabolites by computing the changes in the free energy on mutating key nucleobases in the ligand binding pocket of the riboswitch. We discovered that the electrostatic interactions are central to ligand discrimination by this riboswitch. The relative binding free energies of the mutations further indicated that some of the mutations can also strengthen the binding affinities of the ligands (AZA, UAC, and HPA). These mechanistic details are also potentially relevant in the design of novel compounds targeting riboswitches.
核糖开关是 mRNA 中保守的功能结构域，几乎仅存在于细菌中。它们通过特异性结合小分子，调节氨基酸和必需代谢物（如辅酶、核苷酸碱基及其衍生物）的生物合成和运输。由于其能够精确区分不同的同源分子，以及它们在细菌中的普遍存在，核糖开关已成为潜在的抗菌药物靶点，可以提供具有新型作用机制的急需的抗生素。在这项工作中，我们报告了一种称为核糖开关的 RNA 基序对嘌呤降解过程中产生的四种氧化产物（XAN、AZA、UAC 和 HPA）的识别机制。具体来说，我们通过计算配体结合口袋中关键核苷酸碱基突变时的自由能变化，研究了核糖开关与氧化代谢物之间的物理相互作用。我们发现，静电相互作用是该核糖开关进行配体区分的核心。突变的相对结合自由能进一步表明，一些突变还可以增强配体（AZA、UAC 和 HPA）的结合亲和力。这些机制细节在设计针对核糖开关的新型化合物时也具有潜在的相关性。
