Insights into membrane translocation of the cell-penetrating peptide pVEC from molecular dynamics calculations
Insights into membrane translocation of the cell-penetrating peptide pVEC from molecular dynamics calculations
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DOI：
10.1080/07391102.2015.1117396
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发表时间：
2016-01-01
影响因子：
4.4
通讯作者：
Ozkirimli, Elif
中科院分区：
文献类型：
--
作者：
Alaybeyoglu, Begum;Akbulut, Berna Sariyar;Ozkirimli, Elif
携带细胞穿透肽的货物的发现为开发可以有效靶向细胞内酶的基于肽的药物打开了新的大门。穿膜肽在药物设计中的成功应用和开发取决于对其转运机制的理解。在这项研究中，我们的目的是研究细菌易位机制的细胞穿透pVEC肽（LLIILRRRIRKQAHAHSK）使用转向分子动力学（SMD）模拟。通过对pVEC的丙氨酸突变体和其他变体进行SMD模拟来研究特定残基或区域对于易位的意义。基于残基的分析表明，带正电荷的残基有助于吸附到脂质双层和静电相互作用的脂质双层的肽易位。易位发生在三个主要阶段：N-末端插入双层，整个肽包含在膜内和N-末端离开双层。这三个阶段反映了pVEC上的三个区域;即，疏水性N-末端、阳离子中间部分和亲水性C-末端。N-末端截短的pVEC、I3 A、L5 A、R7 A突变体和乱序pVEC在易位期间与脂质的相互作用较弱，突出了N-末端残基和结构区域的序列对易位机制的贡献。这项研究提供了pVEC肽易位机制的原子细节，可以指导未来的肽为基础的药物设计工作。
Discovery of cargo carrying cell-penetrating peptides has opened a new gate in the development of peptide-based drugs that can effectively target intracellular enzymes. Success in application and development of cell-penetrating peptides in drug design depends on understanding their translocation mechanisms. In this study, our aim was to examine the bacterial translocation mechanism of the cell-penetrating pVEC peptide (LLIILRRRIRKQAHAHSK) using steered molecular dynamics (SMD) simulations. The significance of specific residues or regions for translocation was studied by performing SMD simulations on the alanine mutants and other variants of pVEC. Residue-based analysis showed that positively charged residues contribute to adsorption to the lipid bilayer and to electrostatic interactions with the lipid bilayer as peptides are translocated. Translocation takes place in three main stages; the insertion of the N-terminus into the bilayer, the inclusion of the whole peptide inside the membrane and the exit of the N-terminus from the bilayer. These three stages mirror the three regions on pVEC; namely, the hydrophobic N-terminus, the cationic midsection, and the hydrophilic C-terminus. The N-terminal truncated pVEC, I3A, L5A, R7A mutants and scramble-pVEC make weaker interactions with the lipids during translocation highlighting the contribution of the N-terminal residues and the sequence of the structural regions to the translocation mechanism. This study provides atomistic detail about the mechanism of pVEC peptide translocation and can guide future peptide-based drug design efforts.