Computational study of solution behavior of magainin 2 monomers

Antimicrobial peptides (AMPs) play crucial role as mediators of the primary host defense against microbial invasion. They are considered a promising alternative to antibiotics for multidrug resistant bacterial strains. For complete understanding of the antimicrobial defense mechanism, a detailed knowledge of the dynamics of peptide-membrane interactions, including atomistic studies on AMPs geometry and both peptide and membrane structural changes during the whole process is a prerequisite. We aim at clarifying the conformation dynamics of small linear AMPs in solution as a first step of in silico protocol for establishing a correspondence between certain amino-acid sequence motifs, secondary-structure elements, conformational dynamics in solution and the intensity and mode of interaction with the bacterial membrane. To this end, we use molecular dynamics simulations augmented by well-tempered metadynamics to study the free-energy landscape of two AMPs with close primary structure and different antibacterial activity – the native magainin 2 (MG2) and an analog (MG2m, with substitutions F5Y and F16W) in aqueous solution. We observe that upon solvation, the initial α-helical structures change differently. The native form remains structured, with three shorter α-helical motifs, connected by random coils, while the synthetic analog tends predominantly to a disordered conformation. Our results indicate the importance of the side-chains at positions 5 and 16 for maintaining the solvated peptide conformation. They also provide a modeling background for recent experimental observations, relating the higher α-helical content in solution (peptide pre-folding) in the case of small linear AMPs to a lower antibacterial activity.抗菌肽（Antimicrobial peptides, AMPs）作为宿主抵御微生物入侵的初级防御介质，发挥着至关重要的作用。对于多重耐药细菌菌株而言，它们被视为极具潜力的抗生素替代方案。若要全面阐明抗菌防御机制，需详尽掌握肽-膜相互作用的动力学特性，其中涵盖针对抗菌肽几何结构，以及整个相互作用过程中肽与膜结构变化的原子级研究，这是必要前提。本研究旨在阐明溶液中小分子线性抗菌肽的构象动力学，以此作为计算机模拟研究方案的第一步，以建立特定氨基酸序列基序、二级结构元件、溶液中构象动力学与细菌膜相互作用强度及模式之间的对应关系。为此，我们采用分子动力学模拟结合调温元动力学（well-tempered metadynamics）的方法，研究两种一级结构相近但抗菌活性不同的抗菌肽在水溶液中的自由能景观——天然蛙皮素2（MG2）以及其类似物MG2m（携带F5Y和F16W氨基酸取代）。我们观察到，在溶剂化作用下，初始α-螺旋结构会发生不同程度的变化：天然肽仍保持有序结构，包含三段较短的α-螺旋基序，由无规卷曲连接；而合成类似物则主要倾向于形成无序构象。本研究结果表明，第5和第16位的侧链对于维持溶剂化肽的构象至关重要。本研究同时为近期的实验观测结果提供了建模依据：即小分子线性抗菌肽在溶液中更高的α-螺旋含量（肽预折叠）与其较低的抗菌活性相关联。