Molecular dynamics simulations predict a tilted orientation for the helical region of dynorphin A(1-17) in dimyristoylphosphatidylcholine bilayers.
Molecular dynamics simulations predict a tilted orientation for the helical region of dynorphin A(1-17) in dimyristoylphosphatidylcholine bilayers.
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分子动力学模拟预测二肉豆蔻酰磷脂酰胆碱双层中强啡肽 A(1-17) 螺旋区域的倾斜方向。
DOI：
10.1016/s0006-3495(00)76479-4
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发表时间：
2000
期刊：
影响因子：
--
通讯作者：
Weinstein,H
中科院分区：
文献类型：
--
作者：
Sankararamakrishnan,R;Weinstein,H
用分子动力学模拟方法研究了内源性阿片肽强啡肽强啡肽A(1-17)(DyNA)在二肉豆蔻基磷脂酰胆碱双层膜中的结构性质。从已知的十二烷基磷胆碱胶束中肽的核磁共振结构开始，DyNA的N-末端螺旋片段(包括残基1-10)最初以垂直于膜平面的方向插入到双层中。平行模拟是从两个起始结构A和B开始进行的，这两个结构在多肽螺旋的垂直位置上相差4？该络合物由∼26,400个原子(强啡肽+86种脂类+∼5300水)组成。经过>；2 ns的模拟，其中包括>；1 ns的平衡，在A和B系统中，dyna的螺旋段的取向都经历了从平行到相对于双层法线倾斜的转变。当螺旋轴与双层法线成∼50°角时，在接下来的1 ns模拟中保持稳定。具有不同起点的两个模拟收敛到相同的最终结构，在整个模拟过程中螺旋插入双层。分析表明，N-末端螺旋的倾斜方向是由于dyna序列中的残基与磷脂头基、水和碳氢链的特定相互作用所致。关键因素是精氨酸侧链的“Snorkel模型”类型的相互作用，N-末端疏水序列在脂环境中的稳定性，以及第一残基Tyr的特异性相互作用。浸泡的动力学能促进水在双层内的渗透，但在螺旋的表面并不均匀。许多水分子包围着精氨酸侧链，而疏水残基形成的螺旋表面附近的水渗透可以忽略不计。对于DyNA，提出了一种受体相互作用的机制，涉及从这些模拟中观察到的脂双层中肽的倾斜取向。
The structural properties of the endogenous opioid peptide dynorphin A(1–17) (DynA), a potential analgesic, were studied with molecular dynamics simulations in dimyristoylphosphatidylcholine bilayers. Starting with the known NMR structure of the peptide in dodecylphosphocholine micelles, the N-terminal helical segment of DynA (encompassing residues 1–10) was initially inserted in the bilayer in a perpendicular orientation with respect to the membrane plane. Parallel simulations were carried out from two starting structures, systems A and B, that differ by 4Å in the vertical positioning of the peptide helix. The complex consisted of ∼26,400 atoms (dynorphin+86 lipids+∼5300 waters). After >2ns of simulation, which included >1ns of equilibration, the orientation of the helical segment of DynA had undergone a transition from parallel to tilted with respect to the bilayer normal in both the A and B systems. When the helix axis achieved a ∼50° angle with the bilayer normal, it remained stable for the next 1ns of simulation. The two simulations with different starting points converged to the same final structure, with the helix inserted in the bilayer throughout the simulations. Analysis shows that the tilted orientation adopted by the N-terminal helix is due to specific interactions of residues in the DynA sequence with phospholipid headgroups, water, and the hydrocarbon chains. Key elements are the "snorkel model"-type interactions of arginine side chains, the stabilization of the N-terminal hydrophobic sequence in the lipid environment, and the specific interactions of the first residue, Tyr. Water penetration within the bilayer is facilitated by the immersed DynA, but it is not uniform around the surface of the helix. Many water molecules surround the arginine side chains, while water penetration near the helical surface formed by hydrophobic residues is negligible. A mechanism of receptor interaction is proposed for DynA, involving the tilted orientation observed from these simulations of the peptide in the lipid bilayer.