Molecular dynamics simulations provide structural insight into binding of cyclic dinucleotides to human STING protein

Human stimulator of interferon genes (hSTING) is a signaling adaptor protein that triggers innate immune system by response to cytosolic DNA and second messenger cyclic dinucleotides (CDNs). Natural CDNs contain purine nucleobase with different phosphodiester linkage types (3′-3′, 2′-2′ or mixed 2′-3′-linkages) and exhibit different binding affinity towards hSTING, ranging from micromolar to nanomolar. High-affinity CDNs are considered as suitable candidates for treatment of chronic hepatitis B and cancer. We have used molecular dynamics simulations to investigate dynamical aspects of binding of natural CDNs (specifically, 2'-2'-cGAMP, 2'-3'-cGAMP, 3'-3'-cGAMP, 3'-3'-c-di-AMP, and 3'-3'-c-di-GMP) with hSTINGwt protein. Our results revealed that CDN/hSTINGwt interactions are controlled by the balance between fluctuations (conformational changes) in the CDN ligand and the protein dynamics. Binding of different CDNs induces different degrees of conformational/dynamics changes in hSTINGwt ligand binding cavity, especially in α1-helices, the so-called lid region and α2-tails. The ligand residence time in hSTINGwt protein pocket depends on different contribution of R232 and R238 residues interacting with oxygen atoms of phosphodiester groups in ligand, water distribution around interacting charged centers (in protein residues and ligand) and structural stability of closed conformation state of hSTINGwt protein. These findings may perhaps guide design of new compounds modulating hSTING activity.
Communicated by Ramaswamy H. Sarma

人干扰素基因刺激因子（human stimulator of interferon genes, hSTING）是一种信号衔接蛋白，可通过响应胞质DNA与第二信使环状二核苷酸（cyclic dinucleotides, CDNs）激活先天免疫系统。天然环状二核苷酸带有不同磷酸二酯键连接类型（3′-3′、2′-2′或混合2′-3′连接），其与人干扰素基因刺激因子的结合亲和力范围从微摩尔级至纳摩尔级，存在显著差异。高亲和力环状二核苷酸被认为是治疗慢性乙型肝炎与癌症的潜在候选药物。

本研究采用分子动力学模拟，探究了天然环状二核苷酸（具体包括2'-2'-cGAMP、2'-3'-cGAMP、3'-3'-cGAMP、3'-3'-c-di-AMP以及3'-3'-c-di-GMP）与野生型人干扰素基因刺激因子（hSTINGwt）的结合动力学特性。研究结果表明，环状二核苷酸与野生型人干扰素基因刺激因子的相互作用，受配体自身波动（构象变化）与蛋白动力学之间的动态平衡所调控。不同环状二核苷酸的结合，会使野生型人干扰素基因刺激因子的配体结合口袋产生不同程度的构象/动力学变化，尤其是在α1螺旋、所谓的盖子区域以及α2尾区。配体在野生型人干扰素基因刺激因子蛋白口袋中的停留时间，取决于以下多个因素的共同作用：与配体磷酸二酯基团氧原子发生相互作用的R232与R238残基的贡献、相互作用带电中心（蛋白残基与配体）周围的水分布情况，以及野生型人干扰素基因刺激因子闭合构象状态的结构稳定性。本研究结果可为设计调控人干扰素基因刺激因子活性的新型化合物提供指导思路。

由Ramaswamy H. Sarma转交。