Abstract：
Valinomycin is a potent ionophore known for its ability to transport potassium ions across biological membranes. The study focuses on the hydroxylated analogues of valinomycin (HyVLMs) and compares their energy profiles and capabilities for transporting potassium ions across phospholipid membranes. Using metadynamics, we investigated the energy profiles of wildtype valinomycin (VLM_1) and its three hydroxylated analogues (VLM_2, VLM_3, and VLM_4). We observed that all analogues exhibited energy maxima in the centre of the membrane and preferred positions below the phospholipid heads. Furthermore, the entry barriers for membrane penetration were similar among the analogues, suggesting that the hydroxyl group did not significantly affect their passage through the membrane. Transition state calculations provided insights into the ability of valinomycin analogues to capture potassium ions, with VLM_4 showing the lowest activation energy and VLM_2 displaying the highest. Our findings contribute to understanding the mechanisms of potassium transport by valinomycin analogues and highlight their potential as ionophores. The presence of the hydroxyl group is of particular importance because it paves the way for subsequent chemical modifications and the synthesis of new antiviral agents with reduced intrinsic toxicity.
摘要：
Valinomycin是一种有效的离子载体，以其跨生物膜运输钾离子的能力而闻名。该研究的重点是戊霉素的羟基化类似物（HyVLM），并比较了它们的能量分布和跨磷脂膜运输钾离子的能力。使用元动力学，我们研究了野生型戊霉素（VLM_1）及其三个羟基化类似物（VLM_2，VLM_3和VLM_4）的能量谱。我们观察到所有类似物在膜的中心和磷脂头下方的优选位置表现出能量最大值。此外，膜渗透的进入壁垒在类似物中是相似的，这表明羟基并没有显著影响它们通过膜。过渡态计算提供了对缬霉素类似物捕获钾离子的能力的见解，VLM_4显示最低的活化能，VLM_2显示最高。我们的发现有助于理解缬氨酸霉素类似物的钾转运机制，并强调其作为离子载体的潜力。羟基的存在是特别重要的,因为它为随后的化学修饰和具有降低的固有毒性的新抗病毒剂的合成铺平了道路。
