CREKA (Cys–Arg–Glu–Lys–Ala) and its engineered analogue CRMeEKA, in which Glu has been replaced by N-methyl-Glu to provide resistance against proteolysis, are emerging pentapeptides that were specifically designed to bind fibrin–fibronectin complexes accumulated in the walls of tumour vessels. However, many of the intrinsic properties of CREKA and CRMeEKA, which are probably responsible for their different behaviour when combined with other materials (such as polymers) for diagnosis and therapeutics, remain unknown yet. The intrinsic tendency of these pentapeptides to form aggregates has been analysed by combining experimental techniques and atomistic Molecular Dynamics (MD) simulations. Dynamic light scattering assays show the formation of nanoaggregates that increase in size with the peptide concentration, even though aggregation occurs sooner for CRMeEKA, independently of the peptide concentration. FTIR and circular dichroism spectroscopy studies suggest that aggregated pentapeptides do not adopt any secondary structure. Atomistic MD trajectories show that CREKA aggregates faster and forms bigger molecular clusters than CRMeEKA. This behaviour has been explained by stability of the conformations adopted by un-associated peptide strands. While CREKA molecules organize by forming intramolecular backbone – side chain hydrogen bonds, CRMeEKA peptides display main chain – main chain hydrogen bonds closing very stable γ- or β-turns. Besides, energetic analyses reveal that CRMeEKA strands are better solvated in water than CREKA ones, independent of whether they are assembled or un-associated.

中文翻译：

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治疗性纤维蛋白归巢五肽的聚集倾向：实验和分子动力学模拟的见解

CREKA（Cys–Arg–Glu–Lys–Ala）及其工程类似物CRMeEKA，其中Glu已被N取代-甲基-Glu提供抗蛋白水解的能力，是新兴的五肽，其专门设计用于结合积聚在肿瘤血管壁中的纤维蛋白-纤连蛋白复合物。然而，CREKA和CRMeEKA的许多内在属性可能与它们与其他材料（例如聚合物）结合用于诊断和治疗时的不同行为有关，至今尚不清楚。这些五肽形成聚集体的内在趋势已通过结合实验技术和原子分子动力学（MD）模拟进行了分析。动态光散射测定显示纳米聚集体的形成，纳米聚集体的大小随肽浓度的增加而增加，即使CRMeEKA聚集的发生较早，与肽浓度无关。FTIR和圆二色光谱研究表明，聚集的五肽不采用任何二级结构。原子MD轨迹表明，与CRMeEKA相比，CREKA聚集更快并形成更大的分子簇。这种行为已由未关联的肽链采用的构象的稳定性进行了解释。尽管CREKA分子通过形成分子内主链-侧链氢键而组织起来，但CRMeEKA肽显示的主链-主链氢键闭合非常稳定的γ或β角。此外，能量分析表明，CRMEKEKA链在水中的溶解度比CREKA更好，而与组装或未结合无关。原子MD轨迹表明，与CRMeEKA相比，CREKA聚集更快并形成更大的分子簇。这种行为已由未关联的肽链采用的构象的稳定性进行了解释。尽管CREKA分子通过形成分子内主链-侧链氢键而组织起来，但CRMeEKA肽显示的主链-主链氢键闭合非常稳定的γ或β角。此外，能量分析表明，CRMEKEKA链在水中的溶解度比CREKA更好，而与组装或未结合无关。原子MD轨迹表明，与CRMeEKA相比，CREKA聚集更快并形成更大的分子簇。这种行为已由未关联的肽链采用的构象的稳定性进行了解释。尽管CREKA分子通过形成分子内主链-侧链氢键而组织起来，但CRMeEKA肽显示的主链-主链氢键闭合非常稳定的γ或β角。此外，能量分析表明，CRMEKEKA链在水中的溶解度比CREKA更好，而与组装或未结合无关。CRMeEKA肽显示主链–主链氢键闭合非常稳定的γ或β角。此外，能量分析表明，CRMEKEKA链在水中的溶解度比CREKA更好，而与组装或未结合无关。CRMeEKA肽显示主链–主链氢键闭合非常稳定的γ或β角。此外，能量分析表明，CRMEKEKA链在水中的溶解度比CREKA更好，而与组装或未结合无关。