Interplay of hydrophobic and hydrophilic interactions in sequence-dependent cell penetration of spontaneous membrane-translocating peptides revealed by bias-exchange metadynamics simulations
Interplay of hydrophobic and hydrophilic interactions in sequence-dependent cell penetration of spontaneous membrane-translocating peptides revealed by bias-exchange metadynamics simulations
复制标题
通过偏压交换元动力学模拟揭示自发膜易位肽的序列依赖性细胞渗透中疏水性和亲水性相互作用的相互作用
DOI：
10.1016/j.bbamem.2020.183402
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发表时间：
2020-10-01
影响因子：
3.4
通讯作者：
Zhou, Yaoqi
中科院分区：
文献类型：
--
作者：
Cao, Zanxia;Liu, Lei;Zhou, Yaoqi
自发性膜转位肽（SMTPs）可以沉默地跨双层转位，因此具有改善治疗分子向细胞递送而无毒性的最佳潜力。然而，它们的易位机制如何受到特定肽序列的影响仍然知之甚少。在这里，偏置交换metadaptics模拟调查的5个SMTP具有相同的氨基酸组成（LLRLR，LRLLR，LLLRR，RLLLR，和LRLRL）的易位机制。模拟结果产生序列依赖的自由能垒使用FES沿着z方向的距离。在双层的不同区域的序列依赖性相互作用的深入分析表明，一个特定的序列的自由能垒的高度是由孤立的或成簇的疏水残基（L）和亲水残基（R）的可及性平衡，导致不同水平的阻力移动到膜的疏水中心的肽。在自由能垒的最大值，所有肽具有平行于膜表面的构象，其垒高由它们对疏水区的亲和力决定。适当的双层微扰和GDM（+）配对有利于肽段移位。这些结果为肽序列如何影响转运效率和机制提供了更好的微观理解。
Spontaneous Membrane Translocating Peptides (SMTPs) can translocate silently across the bilayer and, thus, have the best potential to improve the delivery of therapeutic molecules to cells without toxicity. However, how their translocation mechanisms are affected by a specific peptide sequence remains poorly understood. Here, bias-exchange metadynamics simulations were employed to investigate the translocation mechanisms of five SMTPs with the same composition of amino acids (LLRLR, LRLLR, LLLRR, RLLLR, and LRLRL). Simulation results yield sequence-dependent free energy barrier using the FESs along the z-directional distance. An in-depth analysis of sequence-dependent interactions in different regions of the bilayers indicates that the free-energy barrier height of a specific sequence is resulted from the accessibility balance of isolated or clustered hydrophobic residues (L) and hydrophilic residues (R) that leads to different levels of resistance for moving of a peptide into the hydrophobic center of the membrane. At the maximal of the free-energy barrier, all peptides have a conformation parallel to the membrane surface with the barrier height determined by their affinity to the hydrophobic region. The appropriate bilayer perturbation and GDM(+) pairing are beneficial for peptide translocation. These results provide an improved microscopic understanding of how peptide sequence influences the translocation efficiency and mechanism.