The effect of conformation on the solution stability of linear vs. cyclic RGD peptides
The effect of conformation on the solution stability of linear vs. cyclic RGD peptides
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DOI：
10.1034/j.1399-3011.1999.00055.x
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发表时间：
1999-05-01
期刊：
影响因子：
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通讯作者：
Siahaan, TJ
中科院分区：
文献类型：
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作者：
Bogdanowich-Knipp, SJ;Jois, DSS;Siahaan, TJ
本研究的目的是评价线性RGD肽（arg - gly - asp - ph - oh; 1）和环状RGD肽(cyclo-(1,6)- ac - cys - arg - gly - asp - ph - peng - nh2；2);作为ph的函数。先前，人们发现环状肽2比线性肽1稳定30倍。因此，本研究是为了解释基于肽的首选构象的化学稳定性的增加。通过分子动力学模拟和能量最小化来评估两种肽在模拟pH值为3、7和10的水存在条件下的主链柔韧性。模拟过程中还跟踪了两种分子的降解反应位点。线性肽1的主链比环状肽2的主链具有更大的柔韧性，这体现在围绕phi和psi二面角的旋转上。在分子动力学模拟中观察到的结构样品中，肽2的主链原子与肽1的主链原子的低均方根偏差进一步支持了这一点。在模拟的中性pH条件下，Arg和Asp残基的侧链基团之间也存在盐桥。与线性肽1相比，环肽2的稳定性增加，特别是在中性pH下，是由于环施加的结构灵活性降低，以及在环肽2中Arg和Asp残基的侧链之间形成盐桥。这种刚性会阻止Asp侧链羧酸在肽主链上的适当位置定位。
The objective of this study was to evaluate the relationship between conformational flexibility and solution stability of a linear RGD peptide (Arg-Gly-Asp-Phe-OH; 1) and a cyclic RGD peptide (cyclo-(1, 6)-Ac-Cys-Arg-Gly-Asp-Phe-Pen-NH2; 2); as a function of pH. Previously, it was found that cyclic peptide 2 was 30-fold more stable than linear peptide 1. Therefore, this study was performed to explain the increase in chemical stability based on the preferred conformation of the peptides. Molecular dynamics simulations and energy minimizations were conducted to evaluate the backbone flexibility of both peptides under simulated pH conditions of 3, 7 and 10 in the presence of water. The reactive sites for degradation for both molecules were also followed during the simulations. The backbone of linear peptide 1 exhibited more flexibility than that of cyclic peptide 2, which was reflected in the rotation about the phi and psi dihedral angles. This was further supported by the low r.m.s, deviations of the backbone atoms for peptide 2 compared with those of peptide 1 that were observed among structures sampled during the molecular dynamics simulations. The presence of a salt bridge between the side chain groups of the Arg and Asp residues was also indicated for the cyclic peptide under simulated conditions of neutral pH. The increase in stability of the cyclic peptide 2 compared with the linear peptide 1, especially at neutral pH, is due to decreased structural flexibility imposed by the ring, as well as salt bridge formation between the side chains of the Arg and Asp residues in cyclic peptide 2. This rigidity would prevent the Asp side chain carboxylic acid from orienting itself in the appropriate position for attach on the peptide backbone.