Abstract：
Diverse computational approaches have been widely used to assist in designing antimicrobial peptides with enhanced activities. This tactic has also been used to address the need for new treatment alternatives to combat resistant bacterial infections. Herein, we have designed eight variants from a natural peptide, pro-adrenomedullin N-terminal 20 peptide (PAMP), using an in silico pattern insertion approach, the Joker algorithm. All the variants show an α-helical conformation, but with differences in the helix percentages according to circular dichroism (CD) results. We found that the C-terminal portion of PAMP may be relevant for its antimicrobial activities, as revealed by the molecular dynamics, CD, and antibacterial results. The analogs showed variable antibacterial potential, but most were not cytotoxic. Nevertheless, PAMP2 exhibited the most potent activities against human and animal-isolated bacteria, showing cytotoxicity only at a substantially higher concentration than its minimal inhibitory concentration (MIC). Our results suggest that the enhanced activity in the profile of PAMP2 may be related to their particular physicochemical properties, along with the adoption of an amphipathic α-helical arrangement with the conserved C-terminus portion. Finally, the peptides designed in this study can constitute scaffolds for the design of improved sequences.
摘要：
各种计算方法已被广泛用于辅助设计具有增强活性的抗微生物肽。这种策略也被用来解决对新的治疗替代方案的需求，以对抗耐药性细菌感染。在这里，我们设计了8种天然肽的变体,肾上腺髓质素前N末端20肽（PAMP），使用硅片模式插入方法，小丑算法.所有的变体都显示出α-螺旋构象,但根据圆二色性（CD）结果，螺旋百分比存在差异。我们发现PAMP的C端部分可能与其抗菌活性有关，正如分子动力学所揭示的，CD,和抗菌效果。类似物显示出可变的抗菌潜力，但大多数没有细胞毒性。然而，PAMP2对人类和动物分离的细菌表现出最有效的活性，仅在显著高于其最小抑制浓度(MIC)的浓度下显示细胞毒性。我们的结果表明，PAMP2的增强活性可能与其特定的物理化学性质有关，以及采用具有保守C末端部分的两亲性α螺旋排列。最后,本研究中设计的肽可以构成支架，用于设计改进的序列。
