Bromfield Stephen M, Posocco Paola, Fermeglia Maurizio, Tolosa Juan, Herreros-López Ana, Pricl Sabrina, Rodríguez-López Julián, Smith David K
Department of Chemistry, University of York, Heslington, York, YO10 5DD (UK).
Chemistry. 2014 Jul 28;20(31):9666-74. doi: 10.1002/chem.201402237. Epub 2014 Jun 26.
This study investigates transgeden (TGD) dendrimers (polyamidoamine (PAMAM)-type dendrimers modified with rigid polyphenylenevinylene (PPV) cores) and compares their heparin-binding ability with commercially available PAMAM dendrimers. Although the peripheral ligands are near-identical between the two dendrimer families, their heparin binding is very different. At low generation (G1), TGD outperforms PAMAM, but at higher generation (G2 and G3), the PAMAMs are better. Heparin binding also depends strongly on the dendrimer/heparin ratio. We explain these effects using multiscale modelling. TGD dendrimers exhibit "shape-persistent multivalency"; the rigidity means that small clusters of surface amines are locally well optimised for target binding, but it prevents the overall nanoscale structure from rearranging to maximise its contacts with a single heparin chain. Conversely, PAMAM dendrimers exhibit "adaptive multivalency"; the flexibility means individual surface ligands are not so well optimised locally to bind heparin chains, but the nanostructure can adapt more easily and maximise its binding contacts. As such, this study exemplifies important new paradigms in multivalent biomolecular recognition.
本研究调查了反式基因（TGD）树枝状大分子（用刚性聚亚苯基乙烯（PPV）核修饰的聚酰胺胺（PAMAM）型树枝状大分子），并将其肝素结合能力与市售PAMAM树枝状大分子进行比较。尽管这两个树枝状大分子家族的外围配体几乎相同，但它们与肝素的结合却大不相同。在低代数（G1）时，TGD优于PAMAM，但在较高代数（G2和G3）时，PAMAM表现更好。肝素结合也强烈依赖于树枝状大分子/肝素的比例。我们使用多尺度建模来解释这些效应。TGD树枝状大分子表现出“形状持久多价性”；其刚性意味着表面胺的小簇在局部上针对靶标结合进行了良好优化，但它阻止了整体纳米级结构重新排列以最大化其与单个肝素链的接触。相反，PAMAM树枝状大分子表现出“适应性多价性”；其灵活性意味着单个表面配体在局部上与肝素链结合的优化程度不高，但纳米结构可以更容易地适应并最大化其结合接触。因此，本研究例证了多价生物分子识别中的重要新范式。
