Sowlati-Hashjin Shahin, Carbone Paola, Karttunen Mikko
Department of Chemistry, The University of Western Ontario, 1151 Richmond Street, London, Ontario N6A 5B7, Canada.
The Centre of Advanced Materials and Biomaterials Research, The University of Western Ontario, 1151 Richmond Street, London, Ontario N6A 5B7, Canada.
J Phys Chem B. 2020 Jun 4;124(22):4487-4497. doi: 10.1021/acs.jpcb.0c02609. Epub 2020 May 22.
Polyhexamethylene biguanide (PHMB) is a cationic polymer with antimicrobial and antiviral properties. It has been commonly accepted that the antimicrobial activity is due to the ability of PHMB to perforate the bacterial phospholipid membrane leading ultimately to its death. In this study, we show by the means of atomistic molecular dynamics (MD) simulations that, while the PHMB molecules attach to the surface of the phospholipid bilayer and partially penetrate it, they do not cause any pore formation at least within the microsecond simulation times. The polymers initially adsorb onto the membrane surface via the favorable electrostatic interactions between the phospholipid headgroups and the biguanide groups and then partially penetrate the membrane slightly disrupting its structure. This, however, does not lead to the formation of any pores. The microsecond-scale simulations reveal that it is unlikely for PHMB to spontaneously pass through the phospholipid membrane. Our findings suggest that PHMB translocation across the bilayer may take place through binding to the phospholipids. Once inside the cell, the polymer can effectively "bind" to DNA through extensive interactions with DNA phosphate backbone, which can potentially block the DNA replication process or activate DNA repair pathways.
聚六亚甲基双胍（PHMB）是一种具有抗菌和抗病毒特性的阳离子聚合物。人们普遍认为，其抗菌活性是由于PHMB能够穿透细菌磷脂膜，最终导致细菌死亡。在本研究中，我们通过原子分子动力学（MD）模拟表明，虽然PHMB分子附着在磷脂双层表面并部分穿透它，但至少在微秒级模拟时间内它们不会导致任何孔的形成。聚合物最初通过磷脂头部基团与双胍基团之间有利的静电相互作用吸附到膜表面，然后部分穿透膜，轻微破坏其结构。然而，这并不会导致任何孔的形成。微秒级模拟表明，PHMB不太可能自发穿过磷脂膜。我们的研究结果表明，PHMB跨双层转运可能通过与磷脂结合发生。一旦进入细胞，该聚合物可以通过与DNA磷酸骨架的广泛相互作用有效地“结合”到DNA上，这可能会潜在地阻断DNA复制过程或激活DNA修复途径。
