Institute for Molecular Bioscience, The University of Queensland , Brisbane, Queensland 4072, Australia.
J Phys Chem B. 2018 Mar 1;122(8):2261-2276. doi: 10.1021/acs.jpcb.7b12419. Epub 2018 Feb 19.
Several cyclic peptides have been reported to have unexpectedly high membrane permeability. Of these, cyclosporin A is perhaps the most well-known example, particularly in light of its relatively high molecular weight. Observations that cyclosporin A changes conformation depending on its solvent environment led to the hypothesis that conformational dynamics is a prerequisite for its permeability; however, this hypothesis has been difficult to validate experimentally. Here, we use molecular dynamics simulations to explicitly determine the conformational behavior of cyclosporin A and other related cyclic peptides as they spontaneously transition between different environments, including through a lipid bilayer. These simulations are referenced against simulations in explicit water, chloroform, and cyclohexane and further validated against NMR experiments, measuring conformational exchange, nuclear spin relaxation, and three-dimensional structures in membrane-mimicking environments, such as in dodecylphosphocholine micelles, to build a comprehensive understanding of the role of dynamics. We find that conformational flexibility is a key determinant of the membrane permeability of cyclosporin A and similar membrane-permeable cyclic peptides, as conformationally constrained variants have limited movement into, then through, and finally out of the membrane in silico. We envisage that a better understanding of dynamics might thus provide new opportunities to modulate peptide function and enhance their delivery.
已有报道称，一些环状肽具有出人意料的高膜通透性。其中，环孢菌素 A 可能是最著名的例子，尤其是考虑到其相对较高的分子量。环孢菌素 A 的构象会根据其溶剂环境发生变化的观察结果，导致了构象动力学是其通透性的先决条件的假说；然而，这一假说在实验上很难得到验证。在这里，我们使用分子动力学模拟来明确确定环孢菌素 A 和其他相关环状肽在不同环境（包括通过脂质双层）中自发转变时的构象行为。这些模拟与在明水中、氯仿中和环己烷中的模拟进行了对比，并进一步通过 NMR 实验进行了验证，测量了在模拟膜环境中的构象交换、核自旋弛豫和三维结构，如在十二烷基磷酸胆碱胶束中，以建立对动力学作用的全面理解。我们发现，构象灵活性是环孢菌素 A 和类似的可穿透细胞膜的环状肽的膜通透性的关键决定因素，因为构象受限的变体在计算机模拟中在进入、穿过和最终离开膜时的运动受到限制。我们设想，对动力学的更好理解可能会为调节肽功能和增强其递药提供新的机会。
