Quantifying the Effect of Surface Ligands on Dendron-DNA Interactions: Insights into Multivalency through a Combined Experimental and Theoretical Approach

TY - JOUR

T1 - Quantifying the Effect of Surface Ligands on Dendron-DNA Interactions: Insights into Multivalency through a Combined Experimental and Theoretical Approach

AU - Jones, Simon P.

AU - Pavan, Giovanni M.

AU - Danani, Andrea

AU - Pricl, Sabrina

AU - Smith, David K.

PY - 2010/4/19

Y1 - 2010/4/19

N2 - We report the synthesis, DNA binding ability and preliminary gene delivery profiles of dendrons with different amine surface groups, 1,3-diaminopropane (DAP), N,N-di-(3-aminopropyl)-N-(methyl)amine (DAPMA) and spermine (SPM). By using a combination of ethidium bromide displacement, gel electrophoresis and transfection assays, it is shown that the dendrons with SPM groups are the most effective DNA binders, while the DAPMA-functionalised dendrons were the most effective systems for gene delivery (although the gene delivery profiles were still modest). In order to provide deeper insight into the experimental data, we performed a molecular dynamics simulation of the interactions between the dendrons and DNA. The results of these simulations demonstrated that, in general terms, the enthalpic contribution to binding was roughly proportional to the dendron surface charge, but that dendrons with DAP (and DAPMA) surface amities had significant entropic costs of binding to DNA. In the case of DAP, this is a consequence of the fact that the entire dendron structure has to be organised in order for each individual monoamine charge to make effective contact with DNA. For SPM, however, each surface ligand is already a multivalent triamine. therefore. each individual charge has a much lower entropic cost of binding. For DAPMA, we observed that strong binding of the hindered tertiary amine to the DNA double helix led to ligand back-folding and significant geometric distortion of DNA. Although this weakens the overall binding. we suggest that this distortion might be an explanation for the experimentally observed enhanced gene delivery, in which DNA compaction is an important step. Overall, this paper demonstrates how structure activity relationships can be developed for multivalent dendritic ligands and provides insights into the thermodynamics of multivalent interactions.

AB - We report the synthesis, DNA binding ability and preliminary gene delivery profiles of dendrons with different amine surface groups, 1,3-diaminopropane (DAP), N,N-di-(3-aminopropyl)-N-(methyl)amine (DAPMA) and spermine (SPM). By using a combination of ethidium bromide displacement, gel electrophoresis and transfection assays, it is shown that the dendrons with SPM groups are the most effective DNA binders, while the DAPMA-functionalised dendrons were the most effective systems for gene delivery (although the gene delivery profiles were still modest). In order to provide deeper insight into the experimental data, we performed a molecular dynamics simulation of the interactions between the dendrons and DNA. The results of these simulations demonstrated that, in general terms, the enthalpic contribution to binding was roughly proportional to the dendron surface charge, but that dendrons with DAP (and DAPMA) surface amities had significant entropic costs of binding to DNA. In the case of DAP, this is a consequence of the fact that the entire dendron structure has to be organised in order for each individual monoamine charge to make effective contact with DNA. For SPM, however, each surface ligand is already a multivalent triamine. therefore. each individual charge has a much lower entropic cost of binding. For DAPMA, we observed that strong binding of the hindered tertiary amine to the DNA double helix led to ligand back-folding and significant geometric distortion of DNA. Although this weakens the overall binding. we suggest that this distortion might be an explanation for the experimentally observed enhanced gene delivery, in which DNA compaction is an important step. Overall, this paper demonstrates how structure activity relationships can be developed for multivalent dendritic ligands and provides insights into the thermodynamics of multivalent interactions.

KW - dendrimers

KW - DNA

KW - gene technology

KW - molecular dynamics

KW - thermodynamics

KW - ENHANCED TRANSFECTION EFFICIENCY

KW - MOLECULAR-DYNAMICS SIMULATION

KW - VITRO GENE DELIVERY

KW - IN-VITRO

KW - POLYAMIDOAMINE DENDRIMERS

KW - PAMAM DENDRIMER

KW - POLYAMINE-DNA

KW - SUPRAMOLECULAR CHEMISTRY

KW - AMPHIPHILIC DENDRIMERS

KW - COMPUTER-SIMULATION

UR - http://www.scopus.com/inward/record.url?scp=77950835322&partnerID=8YFLogxK

U2 - 10.1002/chem.200902546

DO - 10.1002/chem.200902546

M3 - Article

SN - 0947-6539

VL - 16

SP - 4519

EP - 4532

JO - Chemistry - A European Journal

JF - Chemistry - A European Journal

IS - 15

ER -