Mujika J I, Dalla Torre G, Lachowicz J I, Lopez X
Kimika Fakultatea, Euskal Herriko Unibertsitatea UPV/EHU, Donostia International Physics Center (DIPC) P.K. 1072 20080 Donostia Euskadi Spain
UCBIO/REQUIMTE, Departamento de Química e Bioquímica, Faculdade de Ciências, Universidade do Porto Porto Portugal.
RSC Adv. 2019 Mar 7;9(14):7688-7697. doi: 10.1039/c8ra10139f. eCollection 2019 Mar 6.
The design of new and efficient chelators that can remove aluminium(iii), a metal with increasing recognition as a potential toxic agent, from biological systems is an area of high therapeutic relevance. In the present paper, we present an extensive computational study of a new promising type of these chelators based on mimosine containing peptides. The reason to choose mimosine is that the sidechain of this residue is similar to deferiprone, a ligand known to tightly interact with highly-valent metals, and in particular with Al(iii). In this article we analyze systematically, using a combination of methods that include QM/MM MD simulations, how the size and sequence of the polypeptides can alter the fundamental binding patterns to aluminum, in comparison with the binding to deferiprone. Particular attention is given towards the identification of the smallest peptide that interacts efficiently with aluminum, since polypeptide size is a fundamental factor to allow a given polypeptide to efficiently cross the cell membrane. The results indicate that the longest peptides, with 8 or 9 amino acids, show no difficulties interacting with Al(iii) in an optimum arrangement. By contrast, when the peptide contains five or six amino acids Al(iii) is pentacoordinated, reducing the stability of the resultant complex. In summary, our study demonstrates that the mimosine containing peptides can efficiently coordinate highly valent metals such as Al(iii), with a subtle dependence of the binding on the specific chain-lengths of the polypeptide. We believe that the present study sheds light on the adequacy of this new type of chelator towards aluminum binding.
设计新型高效螯合剂以从生物系统中去除铝（III）是一个具有高度治疗相关性的领域，铝（III）作为一种潜在的有毒金属，其危害性日益受到认可。在本文中，我们对一种基于含含羞草素肽的新型有前景的螯合剂进行了广泛的计算研究。选择含羞草素的原因是该残基的侧链与去铁酮相似，去铁酮是一种已知能与高价金属，特别是与铝（III）紧密相互作用的配体。在本文中，我们系统地分析了多肽的大小和序列如何与去铁酮的结合相比，改变与铝的基本结合模式，采用了包括QM/MM MD模拟在内的多种方法。特别关注鉴定与铝有效相互作用的最小肽，因为多肽大小是使给定多肽有效穿过细胞膜的一个基本因素。结果表明，含有8个或9个氨基酸的最长肽在最佳排列下与铝（III）相互作用没有困难。相比之下，当肽含有5个或6个氨基酸时，铝（III）是五配位的，降低了所得配合物的稳定性。总之，我们的研究表明，含含羞草素的肽可以有效地配位高价金属，如铝（III），其结合对多肽的特定链长有微妙的依赖性。我们相信本研究为这种新型螯合剂对铝结合的适用性提供了启示。
