Unassisted N-acetyl-phenylalanine-amide transport across membrane with varying lipid size and composition: kinetic measurements and atomistic molecular dynamics simulation
Unassisted N-acetyl-phenylalanine-amide transport across membrane with varying lipid size and composition: kinetic measurements and atomistic molecular dynamics simulation
复制标题
具有不同脂质大小和成分的无辅助 N-乙酰基苯丙氨酸酰胺跨膜转运：动力学测量和原子分子动力学模拟
DOI：
10.1080/07391102.2020.1827037
复制
发表时间：
2020
影响因子：
4.4
通讯作者：
Jas, Gouri S.
中科院分区：
文献类型：
--
作者：
Lee, Brent L.;Kuczera, Krzysztof;Lee, Kyung-Hoon;Childs, Ed W.;Jas, Gouri S.
生物膜对于保持结构的完整性和通过对活细胞的营养物质、药物和神经递质的渗透性调节功能特性是必不可少的。研究了乙酰化和酰胺化的苯丙氨酸在1，2-二油酰基-3-甘油-3-磷酸胆碱(DOPC)和1-palmitoyl-2-oleoyl-sn-glycero-3-phosphocholine(POPC)双层膜上的迁移，以探讨其物理传输过程。采用平行人工膜渗透实验(PAMPA)测定了药物的转运速率。生理温度为310 K时，在中性pH下测得的时间常数分别为∼6 h和∼3 h；在酸性条件下，pH为4.8时，两种脂类的时间常数均为∼8 h。在计算上，我们扩展了我们对三个芳香族二肽在DOPC18组成的双层中的转运研究。在这项研究中，我们通过模拟二肽在三个不同的双层中，50个DOPC脂类，50个POPC脂类和40个POPC分子，研究了脂组成和双层大小对NAFA被动转运的影响。具体地说，采用伞状取样的原子分子动力学模拟方法计算了NaFA在两层膜中被动渗透的平均作用力势。然后通过数值求解Smoluchowski方程来计算扩散常数。然后计算了渗透系数和平均首次通过时间。结构性质-Ramachandran图、侧链扭转、多肽插入角、径向分布函数和近端多肽水分子-也被检测以确定系统大小和脂质类型的影响。在体系大小方面，我们观察到平均作用力势的最高势垒略有下降，由于较小的脂双层内较弱的膜变形，具有40个与50个POPC脂类的侧链二面角构象采样较少。在脂质类型方面，DOPC含有两个单不饱和的酰基链，而POPC中只有一个这样的酰基链；因此，DOPC双层分子的有序性较差，更容易变形，这从平均作用力分布的更广泛的势可以看出。与POPC相比，DOPC脂质中的NaFA在更低的膜深度处也转变为内部氢键主干构象。类似地，对于其他芳香族二肽，在DOPC和POPC中，NAFA倾向于先插入膜的侧链，在膜中心大部分保持脱溶，并且在双层内表现出缓慢的重定向。通过联合实验和计算研究，我们对最简单的疏水性芳香族二肽在不同脂双层条件下的转运速率和潜在的微观机制有了新的认识。
Biological membranes are essential to preserve structural integrity and regulate functional properties through the permeability of nutrients, pharmaceutical drugs, and neurotransmitters of a living cell. The movement of acetylated and amidated phenylalanine (NAFA) across 1,2-dioleoyl-sn-glycero-3-phosphocholine (DOPC) and 1-palmitoyl-2-oleoyl-sn-glycero-3-phosphocholine (POPC) membrane bilayers is investigated to probe physical transport. The rate of transport is measured experimentally applying parallel artificial membrane permeation assay (PAMPA). At the physiological temperature, 310 K, the measured time constants in the neutral pH were ∼6 h in DOPC and ∼3 h in POPC, while in a more acidic condition, at a pH 4.8, the time constants were ∼8 h in both lipids. Computationally, we have expanded our transport study of three aromatic dipeptides across a bilayer composed of DOPC18. In this study, we have examined the effects of lipid composition and bilayer size on the passive transport of NAFA by simulating the dipeptide in three different bilayers, with 50 DOPC lipids, 50 POPC lipids, and 40 POPC molecules. Specifically, atomistic molecular dynamics simulations with umbrella sampling were used to calculate the potential of mean force for the passive permeation of NAFA across the bilayers. Diffusion constants were then calculated by numerically solving the Smoluchowski equation. Permeability coefficients and mean first passage times were then calculated. Structural properties – Ramachandran plots, sidechain torsions, peptide insertion angles, radial distribution functions, and proximal peptide water molecules – were also examined to determine the effect of system size and lipid type. In terms of systems size, we observed a small decrease in the highest barrier of the potential of mean force and fewer sampled sidechain dihedral angle conformations with 40 versus 50 POPC lipids due to weaker membrane deformations within a smaller lipid bilayer. In terms of lipid type, DOPC contains two monounsaturated acyl chains compared to only one such acyl chain in POPC; therefore, DOPC bilayers are less ordered and more easily deformed, as seen by a much broader potential of mean force profile. The NAFA in DOPC lipid also transitioned to an internally hydrogen-bonded backbone conformation at lower membrane depths than in POPC. Similarly, as for other aromatic dipeptides, NAFA tends to insert into the membrane sidechain-first, remains mostly desolvated in the membrane center, and exhibits slow reorientations within the bilayer in both DOPC and POPC. With a joint experimental and computational study we have gained a new insight into the rate of transport and the underlying microscopic mechanism in different lipid bilayer conditions of the simplest hydrophobic aromatic dipeptide.Communicated by Ramaswamy H. Sarma
登录
查看更多内容
DOI：
10.1021/jz200167q
发表时间：
2011
期刊：
The journal of physical chemistry letters
影响因子：
--
作者：
Pastor RW;Mackerell AD Jr
通讯作者：
Mackerell AD Jr
影响因子：
3.3
作者：
Wei, Chenyu;Pohorille, Andrew
通讯作者：
Pohorille, Andrew
芳香族氨基酸及其侧链模型的重新取向：各向异性测量和分子动力学模拟。
影响因子：
2.9
作者：
K. Kuczera;J. Unruh;Carey K. Johnson;G. Jas
通讯作者：
G. Jas
影响因子：
4.4
作者：
R. Venable;B. Brooks;R. Pastor
通讯作者：
R. Venable;B. Brooks;R. Pastor
影响因子：
3.4
作者：
K. Tu;Douglas J. Tobias;J. Blasie;Michael L. Klein
通讯作者：
K. Tu;Douglas J. Tobias;J. Blasie;Michael L. Klein