Shape-persistent and adaptive multivalency: Rigid transgeden (TGD) and flexible PAMAM dendrimers for heparin binding

TY - JOUR

T1 - Shape-persistent and adaptive multivalency

T2 - Rigid transgeden (TGD) and flexible PAMAM dendrimers for heparin binding

AU - Bromfield, Stephen M.

AU - Posocco, Paola

AU - Fermeglia, Maurizio

AU - Tolosa, Juan

AU - Herreros-López, Ana

AU - Pricl, Sabrina

AU - Rodríguez-López, Julián

AU - Smith, David K.

N1 - © 2014, WILEY-VCH Verlag GmbH & Co. This is an author-produced version of the published paper. Uploaded in accordance with the publisher’s self-archiving policy. Further copying may not be permitted; contact the publisher for details

PY - 2014/7/28

Y1 - 2014/7/28

N2 - 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. Movers and shakers: The inside of the dendrimer controls the display of the surface ligands. Rigid TGDs (shown in red) have locally organised shape-persistent multivalent surface groups that can only bind well if several different heparin chains are present to satisfy all the rigidly displayed surface groups, whereas PAMAMs (shown in green) have flexible structures that show adaptive multivalency to wrap around a single heparin chain.

AB - 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. Movers and shakers: The inside of the dendrimer controls the display of the surface ligands. Rigid TGDs (shown in red) have locally organised shape-persistent multivalent surface groups that can only bind well if several different heparin chains are present to satisfy all the rigidly displayed surface groups, whereas PAMAMs (shown in green) have flexible structures that show adaptive multivalency to wrap around a single heparin chain.

KW - dendrimers

KW - heparin

KW - molecular recognition

KW - multiscale molecular modeling

KW - multivalency

UR - http://www.scopus.com/inward/record.url?scp=84905660719&partnerID=8YFLogxK

U2 - 10.1002/chem.201402237

DO - 10.1002/chem.201402237

M3 - Article

AN - SCOPUS:84905660719

SN - 0947-6539

VL - 20

SP - 9666

EP - 9674

JO - Chemistry - A European Journal

JF - Chemistry - A European Journal

IS - 31

ER -