Molecular Simulations of Polycation鈥揇NA Binding Exploring the Effect of Peptide Chemistry and Sequence in Nuclear Localization Sequence Based Polycations

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• 作者：Robert M. Elder ; Arthi Jayaraman
• 刊名：Journal of Physical Chemistry B
• 出版年：2013
• 出版时间：October 10, 2013
• 年：2013
• 卷：117
• 期：40
• 页码：11988-11999
• 全文大小：420K
• 年卷期：v.117,no.40(October 10, 2013)
• ISSN：1520-5207

文摘

Gene therapy relies on the delivery of DNA into cells, and polycations are one class of vectors enabling efficient DNA delivery. Nuclear localization sequences (NLS), cationic oligopeptides that target molecules for nuclear entry, can be incorporated into polycations to improve their gene delivery efficiency. We use simulations to study the effect of peptide chemistry and sequence on the DNA-binding behavior of NLS-grafted polycations by systematically mutating the residues in the grafts, which are based on the SV40 NLS (peptide sequence PKKKRKV). Replacing arginine (R) with lysine (K) reduces binding strength by eliminating arginine鈥揇NA interactions, but placing R in a less hindered location (e.g., farther from the grafting point to the polycation backbone) has surprisingly little effect on polycation鈥揇NA binding strength. Changing the positions of the hydrophobic proline (P) and valine (V) residues relative to the polycation backbone changes hydrophobic aggregation within the polycation and, consequently, changes the conformational entropy loss that occurs upon polycation鈥揇NA binding. Since conformational entropy loss affects the free energy of binding, the positions of P and V in the grafts affect DNA binding affinity. The insight from this work guides synthesis of polycations with tailored DNA binding affinity and, in turn, efficient DNA delivery.