Porto William F, Alencar Sergio A
Porto Reports, Brasília, DF, Brazil; Programa de Pós-Graduação em Ciências Genômicas e Biotecnologia, Universidade Católica de Brasília, Brasília, DF, Brazil.
Programa de Pós-Graduação em Ciências Genômicas e Biotecnologia, Universidade Católica de Brasília, Brasília, DF, Brazil.
J Mol Graph Model. 2023 Jan;118:108368. doi: 10.1016/j.jmgm.2022.108368. Epub 2022 Oct 28.
Cathelicidin antimicrobial peptides are a diverse family of cationic amphipathic peptides with multiple activities. In humans, cathelicidin LL-37 is one of the main host defense peptides with a remarkable medical and biotechnological potential. Deregulation of LL-37 expression has been associated with inflammatory diseases. However the effects of point mutations driven by single nucleotide polymorphisms (SNPs) on LL-37 are unknown. Here we applied an array of computational tools to investigate the effects of such mutations on LL-37 structure and activity. Due to the fact that, on cathelicidins, the prodomain is more conserved than the mature peptide, the SNP effect predictions were biased and, overall, resulted in neutral effects; and due to the slight changes in physicochemical properties, the antimicrobial predictions indicated the maintenance of such activity. Nonetheless, R07P, R07W, R29Q, R29W mutations reduced the peptide net charge, which in turn could result in less active LL-37 variants. Molecular dynamics data indicated that R07Q and N30Y mutations altered the LL-37 structure, leading to potential deleterious effects. In addition, the helix dipole is altered in G03A, R07P, R07W and L31P mutations, which could also alter the antimicrobial activity. Our results indicated that despite the mutations did not alter the residues from LL-37 active core, they could influence the antimicrobial activity and consequently, could be involved in inflammatory diseases.
杀菌肽抗菌肽是一类具有多种活性的阳离子两亲性肽的多样化家族。在人类中，杀菌肽LL-37是主要的宿主防御肽之一，具有显著的医学和生物技术潜力。LL-37表达失调与炎症性疾病有关。然而，单核苷酸多态性（SNP）驱动的点突变对LL-37的影响尚不清楚。在这里，我们应用了一系列计算工具来研究此类突变对LL-37结构和活性的影响。由于在杀菌肽上，前结构域比成熟肽更保守，SNP效应预测存在偏差，总体上产生中性效应；并且由于物理化学性质的轻微变化，抗菌预测表明这种活性得以维持。尽管如此，R07P、R07W、R29Q、R29W突变降低了肽的净电荷，这反过来可能导致活性较低的LL-37变体。分子动力学数据表明，R07Q和N30Y突变改变了LL-37的结构，导致潜在的有害影响。此外，G03A、R07P、R07W和L31P突变改变了螺旋偶极，这也可能改变抗菌活性。我们的结果表明，尽管这些突变没有改变LL-37活性核心的残基，但它们可能影响抗菌活性，因此可能与炎症性疾病有关。
