The complement system plays a major role in human immunity, but its abnormal activation can have severe pathological impacts. By mimicking a natural mechanism of complement regulation, the small peptide compstatin has proven to be a very promising complement inhibitor. Over the years, several compstatin analogs have been created, with improved inhibitory potency. A recent analog is being developed as a candidate drug against several pathological conditions, including COVID-19. However, the reasons behind its higher potency and increased binding affinity to complement proteins are not fully clear. This computational study highlights the mechanistic properties of several compstatin analogs, thus complementing previous experimental studies. We perform molecular dynamics simulations involving six analogs alone in solution and two complexes with compstatin bound to complement component 3. These simulations reveal that all the analogs we consider, except the original compstatin, naturally adopt a pre-bound conformation in solution. Interestingly, this set of analogs adopting a pre-bound conformation includes analogs that were not known to benefit from this behavior. We also show that the most recent compstatin analog (among those we consider) forms a stronger hydrogen bond network with its complement receptor than an earlier analog.

中文翻译：

---

使用分子动力学对补体抑制剂康普他汀进行计算分析。

补体系统在人体免疫中起主要作用，但其异常激活会产生严重的病理影响。通过模仿补体调节的自然机制，小肽康普他汀已被证明是一种非常有前途的补体抑制剂。多年来，已经产生了几种具有改进抑制效力的康普他汀类似物。最近正在开发一种类似物作为针对多种病理状况的候选药物，包括 COVID-19。然而，其更高效力和增加与补体蛋白的结合亲和力背后的原因尚不完全清楚。这项计算研究突出了几种康普他汀类似物的机械特性，从而补充了以前的实验研究。我们进行了分子动力学模拟，涉及溶液中单独的六个类似物和两个与 compstatin 结合以补充组分 3 的复合物。这些模拟表明，我们考虑的所有类似物，除了原始 compstatin，在溶液中自然采用预结合构象。有趣的是，这组采用预结合构象的类似物包括不知道会从这种行为中受益的类似物。我们还表明，最新的康普他汀类似物（在我们考虑的那些中）与其补体受体形成了比早期类似物更强的氢键网络。