Antimicrobial peptides (AMPs) are molecules found in most organisms, playing a vital role in innate immune defense against pathogens. Their mechanism of action involves the disruption of bacterial cell membranes, causing leakage of cellular contents and ultimately leading to cell death. While AMPs typically lack a defined structure in solution, they often assume a defined conformation when interacting with bacterial membranes. Given this structural flexibility, we investigated whether intrinsically disordered regions (IDRs) with AMP-like properties could exhibit antimicrobial activity. We tested 14 peptides from different IDRs predicted to have antimicrobial activity and found that nearly all of them did not display the anticipated effects. These peptides failed to adopt a defined secondary structure and had compromised membrane interactions, resulting in a lack of antimicrobial activity. We hypothesize that evolutionary constraints may prevent IDRs from folding, even in membrane-like environments, limiting their antimicrobial potential. Moreover, our research reveals that current antimicrobial predictors fail to accurately capture the structural features of peptides when dealing with intrinsically unstructured sequences. Hence, the results presented here may have far-reaching implications for designing and improving antimicrobial strategies and therapies against infectious diseases.

中文翻译：

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预测的局限性：为什么本质上无序的区域挑战我们对抗菌肽的理解

抗菌肽 (AMP) 是在大多数生物体中发现的分子，在针对病原体的先天免疫防御中发挥着至关重要的作用。它们的作用机制涉及破坏细菌细胞膜，导致细胞内容物泄漏并最终导致细胞死亡。虽然 AMP 在溶液中通常缺乏确定的结构，但它们在与细菌膜相互作用时通常呈现确定的构象。鉴于这种结构灵活性，我们研究了具有类似 AMP 特性的本质无序区域 (IDR) 是否可以表现出抗菌活性。我们测试了来自不同 IDR 的 14 种预计具有抗菌活性的肽，发现几乎所有肽都没有表现出预期的效果。这些肽未能采用明确的二级结构，并且膜相互作用受损，导致缺乏抗菌活性。我们假设进化限制可能会阻止 IDR 折叠，即使在膜状环境中也是如此，从而限制了它们的抗菌潜力。此外，我们的研究表明，当前的抗菌预测因子在处理本质上非结构化的序列时无法准确捕获肽的结构特征。因此，这里提出的结果可能对设计和改进针对传染病的抗菌策略和疗法具有深远的影响。