Institute of Biophysics and Department of Physics, Central China Normal University, Wuhan, 430079, China.
State Key Laboratory of Magnetic Resonance and Atomic Molecular Physics, Innovation Academy for Precision Measurement Science and Technology Chinese Academy of Sciences, Wuhan, Hubei 430071, China.
Phys Chem Chem Phys. 2023 Oct 25;25(41):27967-27980. doi: 10.1039/d3cp03384h.
Designing inhibitors for RNA is still challenging due to the bottleneck of maintaining the binding interaction of inhibitor-RNA accompanied by subtle RNA flexibility. Thus, the current approach usually needs to screen thousands of candidate inhibitors for binding. Here, we propose a dynamic geometry design approach to enrich the hits with only a tiny pool of designed geometrically compatible scaffold candidates. First, our method uses graph-based tree decomposition to explore the complementarity rigid binding cyclic peptide and design the amino acid side chain length and charge to fit the RNA pocket. Then, we perform an energy-based dynamical network algorithm to optimize the inhibitor-RNA hydrogen bonds. Dynamic geometry-guided design yields successful inhibitors with low micromolar binding affinity scaffolds and experimentally competes with the natural RNA chaperone. The results indicate that the dynamic geometry method yields higher efficiency and accuracy than traditional methods. The strategy could be further optimized to design the length and chirality by adopting nonstandard amino acids and facilitating RNA engineering for biological or medical applications.
由于需要保持抑制剂-RNA 的结合相互作用，同时伴随着 RNA 微小的灵活性，因此设计 RNA 的抑制剂仍然具有挑战性。因此，目前的方法通常需要筛选数千种候选抑制剂以进行结合。在这里，我们提出了一种动态几何设计方法，仅用一小部分设计的几何相容支架候选物来丰富命中。首先，我们的方法使用基于图的树分解来探索互补刚性结合的环状肽，并设计氨基酸侧链长度和电荷以适应 RNA 口袋。然后，我们执行基于能量的动力学网络算法来优化抑制剂-RNA 的氢键。动态几何引导设计产生了具有低微摩尔结合亲和力支架的成功抑制剂，并在实验上与天然 RNA 伴侣竞争。结果表明，动态几何方法比传统方法具有更高的效率和准确性。该策略可以通过采用非标准氨基酸进一步优化设计长度和手性，并促进 RNA 工程在生物或医学应用中的应用。
