Nanoscopic Structure of Complexes Formed between DNA and the Cell-Penetrating Peptide Penetratin

被引:17
作者
de Mello, Lucas Rodrigues [1 ]
Hamley, Ian William [2 ]
Castelletto, Valeria [2 ]
Moreno Garci, Bianca Bonetto [1 ]
Han, Sang Won [1 ]
Pinto de Oliveira, Cristiano Luis [3 ]
da Silv, Emerson Rodrigo a [1 ]
机构
[1] Univ Fed Sao Paulo, Dept Biofis, BR-04023062 Sao Paulo, Brazil
[2] Univ Reading, Dept Chem, Reading RGD 6AD, Berks, England
[3] Univ Sao Paulo, Inst Fis, BR-05508090 Sao Paulo, Brazil
基金
巴西圣保罗研究基金会; 英国工程与自然科学研究理事会;
关键词
ARGININE-RICH PEPTIDES; GENE DELIVERY; IN-VITRO; MEMBRANE; HOMEODOMAIN; SCATTERING; SOLVATION; MECHANISM; LENGTH;
D O I
10.1021/acs.jpcb.9b05512
中图分类号
O64 [物理化学(理论化学)、化学物理学];
学科分类号
070304 ; 081704 ;
摘要
One of the most remarkable examples of cell-penetrating peptides (CPPs) is Penetratin, a 16-mer fragment derived from the Drosophila Antennapedia homeobox. Understanding the structure of Penetratin/DNA complexes is a key factor for the successful design of new vectors for gene delivery and may assist in optimizing molecular carriers based on CPPs. Herein, we present a comprehensive study on the nanoscale structure of noncovalent complexes formed between Penetratin and DNA. The strong cationic nature of the peptide makes it a very efficient agent for condensing DNA strands via electrostatic attraction, and we show for the first time that DNA condensation is accompanied by random-to-beta-sheet transitions of Penetratin secondary structure, demonstrating that nucleic acids behave as a structuring agent upon complexation. For the first time, nanoscale-resolved spectroscopy is used to provide single-particle infrared data from DNA carriers based on CPPs, and they show that the structures are stabilized by Penetratin beta-sheet cores, whereas larger DNA fractions are preferentially located in the periphery of aggregates. In-solution infrared assays indicate that phosphate diester groups are strongly affected upon DNA condensation, presumably as a consequence of charge delocalization induced by the proximity of cationic amide groups in Penetratin. The morphology is characterized by nanoassemblies with surface fractal features, and short-range order is found in the inner structure of the scaffolds. Interestingly, the formation of beads-on-a-string arrays is found, producing nanoscale architectures that resemble structures observed in early steps of chromatin condensation. A complexation pathway where DNA condensation and peptide pairing into beta-sheets are key steps for organization is proposed.
引用
收藏
页码:8861 / 8871
页数:11
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