Zanuy David, Flores-Ortega Alejandra, Casanovas Jordi, Curcó David, Nussinov Ruth, Alemán Carlos
Departament d'Enginyeria Química, E. T. S. d'Enginyeria Industrial de Barcelona, Universitat Politècnica de Catalunya, Diagonal 647, Barcelona E-08028, Spain.
J Phys Chem B. 2008 Jul 24;112(29):8692-700. doi: 10.1021/jp711477k. Epub 2008 Jun 28.
Recently, a potentially powerful strategy based on phage-display libraries has been presented to target tumors via homing peptides attached to nanoparticles. The Cys-Arg-Glu-Lys-Ala (CREKA) peptide sequence has been identified as a tumor-homing peptide that binds to clotted plasmas proteins present in tumor vessels and interstitium. The aim of this work consists of mapping the conformational profile of CREKA to identify the bioactive conformation. For this purpose, a conformational search procedure based on modified simulated annealing combined with molecular dynamics was applied to three systems that mimic the experimentally used conditions: (i) the free peptide; (ii) the peptide attached to a nanoparticle; and (iii) the peptide inserted in a phage display protein. In addition, the free peptide was simulated in an ionized aqueous solution environment, which mimics the ionic strength of the physiological medium. Accessible minima of all simulated systems reveal a multiple interaction pattern involving the ionized side chains of Arg, Glu, and Lys, which induces a beta-turn motif in the backbone observed in all simulated CREKA systems.
最近，一种基于噬菌体展示文库的潜在强大策略已被提出，即通过附着在纳米颗粒上的归巢肽靶向肿瘤。半胱氨酸-精氨酸-谷氨酸-赖氨酸-丙氨酸（CREKA）肽序列已被鉴定为一种肿瘤归巢肽，它能与肿瘤血管和间质中存在的凝血血浆蛋白结合。这项工作的目的是绘制CREKA的构象图谱，以确定其生物活性构象。为此，将基于改进模拟退火结合分子动力学的构象搜索程序应用于三个模拟实验所用条件的系统：（i）游离肽；（ii）附着在纳米颗粒上的肽；（iii）插入噬菌体展示蛋白中的肽。此外，在模拟生理介质离子强度的离子化水溶液环境中模拟游离肽。所有模拟系统可及的最小值揭示了一种涉及精氨酸、谷氨酸和赖氨酸离子化侧链的多重相互作用模式，这在所有模拟的CREKA系统的主链中诱导出一个β-转角基序。
