Molecular dynamics and circular dichroism studies of human and rat C-peptides
Molecular dynamics and circular dichroism studies of human and rat C-peptides
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DOI：
10.1016/j.jmgm.2006.03.002
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发表时间：
2006-12-01
影响因子：
2.9
通讯作者：
Santoro, Marcelo Matos
中科院分区：
文献类型：
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作者：
Mares-Guia, Thiago Renno;Maigret, Bernard;Santoro, Marcelo Matos
胰岛素原C-肽最近被认为是一种内源性多肽激素，除了在胰岛素原的加工过程中发挥作用外，还具有重要的生理功能。越来越多的证据表明，C-肽在I型糖尿病患者长期并发症的治疗中发挥了有益的作用，这表明该分子可能在未来的治疗中与胰岛素一起使用。尽管有明确的药理意义，但人类C肽的二级和三维结构仍然是争议的焦点。在目前的工作中，我们报告了对人、大鼠I和大鼠II C肽的分子动力学(MD)模拟。一种适用于所有多肽的共同实验策略包括同源构建，然后在真空和水中进行多秒MD模拟。在没有和存在2，2，2-三氟乙醇(TFE)的情况下，对每个多肽进行了圆二色谱(CD)实验，以支持理论模型的验证。构建了23个已知哺乳动物C-肽的多个序列比对，以确定对维持二级和三级结构重要的重要保守位点。对人、大鼠I和大鼠II分子的分子动力学轨迹分析显示出非常不同的一般行为，人C肽比其他两个分子更灵活。人和大鼠的C-肽在中间和C-末端显示出非常稳定的转折结构，这被认为是C-肽的潜在活性部位。人C-肽在整个MD也呈现一个短的α-螺旋，这是在大鼠分子中没有发现的。CD数据与MD结果非常一致，两种方法都能够识别出比人C肽更大的结构稳定性和潜力。根据多序列比对、最近文献中的实验数据和我们自己的CD实验，对模拟结果进行了讨论和验证。(C)2006年，由爱思唯尔公司出版。
Proinsulin C-peptide has been recently described as an endogenous peptide hormone, responsible for important physiological functions others than its role in proinsulin processing. Accumulating evidences that C-peptide exerts beneficial effects in the treatment of long term complications of patients with type I diabetes mellitus indicate that this molecule may be administered together with insulin in future therapies. Despite its clear pharmacological interest, the secondary and three-dimensional (3D) structures of human C-peptide are still points of controversy. In the present work we report molecular dynamics (MD) simulations of human, rat I and rat II C-peptides. A common experimental strategy applied to all peptides consisted of homology building followed by multinanosecond MD simulations in vacuum and water. Circular dichroism (CD) experiments of each peptide in the absence and presence of 2,2,2-trifluoroethanol (TFE) were performed to support validation of the theoretical models. A multiple sequence alignment of 23 known mammalian C-peptides was constructed to identify significant conserved sites that would be important for the maintenance of secondary and tertiary structures. The analysis of the molecular dynamics trajectories for the human, rat I and rat II molecules have shown quite different general behavior, being the human C-peptide more flexible than the two others. Human and rat C-peptides exhibit very stable turn-like structures at the middle and C-terminal regions, which have been described as potential active sites of C-peptides. Human C-peptide also presented a short alpha-helix throughout the MD, which was not found in the rat molecules. CD data is in very good agreement with the MD results and both methods were able to identify a greater structural stability and potential in rat C-peptides when compared to the human C-peptide. The simulation results are discussed and validated in the light of multiple sequence alignment, recent experimental data from the literature and our own CD experiments. (c) 2006 Published by Elsevier Inc.