Dreab Ana, Bayse Craig A
Department of Chemistry and Biochemistry, Old Dominion University Norfolk VA 23529 USA.
RSC Chem Biol. 2023 Jun 7;4(8):573-586. doi: 10.1039/d3cb00035d. eCollection 2023 Aug 3.
Metalation of the N-terminal Amino Terminal Cu(ii)- and Ni(ii)-binding (ATCUN) motif may enhance the antimicrobial properties of piscidins. Molecular dynamics simulations of free and nickelated piscidins 1 and 3 (P1 and P3) were performed in 3 : 1 POPC/POPG and 2.6 : 1 : 0.4 POPC/POPG/aldo-PC bilayers (POPC, 1-palmitoyl-2-oleoyl--glycero-3-phosphocholine: POPG, 1-palmitoyl-2-oleoyl--glycero-3-phosphoglycerol; aldo-PC, 1-palmitoyl-2-(9'-oxo-nonanoyl)--glycero-3-phosphocholine) bilayer models. Nickel(ii) binding decreases the conformation dynamics of the ATCUN motif and lowers the charge of the N-terminus to allow it to embed deeper in the bilayer without significantly changing the overall depth due to interactions of the charged half-helix of the peptide with the headgroups. Phe1⋯Ni cation-π and Phe2-Phe1 CH-π interactions contribute to a small fraction of structures within the nickelated P1 simulations and may partially protect a bound metal from metal-centered chemical activity. The substitution of Phe2 for Ile2 in P3 sterically blocks conformations with cation-π interactions offering less protection to the metal. This difference between metalated P1 and P3 may indicate a mechanism by which peptide sequence can influence antimicrobial properties. Any loss of bilayer integrity due to chain reversal of the oxidized phospholipid chains of aldo-PC may be enhanced in the presence of metalated piscidins.
N 端氨基末端铜（II）和镍（II）结合（ATCUN）基序的金属化可能会增强鱼抗菌肽的抗菌特性。在 3∶1 的 POPC/POPG 和 2.6∶1∶0.4 的 POPC/POPG/醛基磷脂酰胆碱（POPC，1 - 棕榈酰 - 2 - 油酰 - sn - 甘油 - 3 - 磷酸胆碱；POPG，1 - 棕榈酰 - 2 - 油酰 - sn - 甘油 - 3 - 磷酸甘油；醛基磷脂酰胆碱，1 - 棕榈酰 - 2 -（9'- 氧代壬酰）- sn - 甘油 - 3 - 磷酸胆碱）双层模型中，对游离的和镍化的鱼抗菌肽 1 和 3（P1 和 P3）进行了分子动力学模拟。镍（II）结合降低了 ATCUN 基序的构象动力学，并降低了 N 端的电荷，使其能够更深地嵌入双层中，同时由于肽的带电半螺旋与头部基团的相互作用，不会显著改变整体深度。Phe1⋯Ni 阳离子 - π 和 Phe2 - Phe1 CH - π 相互作用在镍化的 P1 模拟中的一小部分结构中起作用，并且可能部分保护结合的金属免受以金属为中心的化学活性影响。在 P3 中用 Ile2 取代 Phe2 在空间上阻碍了具有阳离子 - π 相互作用的构象，对金属的保护作用较小。金属化的 P1 和 P3 之间的这种差异可能表明一种肽序列可以影响抗菌特性的机制。在存在金属化鱼抗菌肽的情况下，由于醛基磷脂酰胆碱的氧化磷脂链的链反转导致的双层完整性的任何损失可能会增强。
