Sessa Lucia, Concilio Simona, Marrafino Francesco, Sarkar Arkadeep, Diana Rosita, Piotto Stefano
Department of Pharmacy, University of Salerno, Via Giovanni Paolo II 132, 84084 Fisciano, SA, Italy; Bionam Research Centre for Biomaterials, University of Salerno, Via Giovanni Paolo II 132, 84084 Fisciano, SA, Italy.
Department of Pharmacy, University of Salerno, Via Giovanni Paolo II 132, 84084 Fisciano, SA, Italy; Bionam Research Centre for Biomaterials, University of Salerno, Via Giovanni Paolo II 132, 84084 Fisciano, SA, Italy.
Comput Biol Chem. 2023 Oct;106:107936. doi: 10.1016/j.compbiolchem.2023.107936. Epub 2023 Jul 28.
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.
缬氨霉素是一种强效离子载体，以其跨生物膜转运钾离子的能力而闻名。该研究聚焦于缬氨霉素的羟基化类似物（HyVLMs），并比较了它们的能量分布以及跨磷脂膜转运钾离子的能力。利用元动力学，我们研究了野生型缬氨霉素（VLM_1）及其三种羟基化类似物（VLM_2、VLM_3和VLM_4）的能量分布。我们观察到，所有类似物在膜中心均呈现能量最大值，且偏好位于磷脂头部下方的位置。此外，各类似物的膜穿透进入障碍相似，这表明羟基并未显著影响它们通过膜的过程。过渡态计算为缬氨霉素类似物捕获钾离子的能力提供了见解，其中VLM_4显示出最低的活化能，而VLM_2显示出最高的活化能。我们的研究结果有助于理解缬氨霉素类似物的钾转运机制，并突出了它们作为离子载体的潜力。羟基的存在尤为重要，因为它为后续的化学修饰以及合成具有降低内在毒性的新型抗病毒药物铺平了道路。
