Gamma PNA
Abstract: Peptide nucleic acid (PNA) is a synthetic analogue of DNA and RNA, developed more than a decade ago in which the naturally occurring sugar phosphate backbone has been replaced by the N-(2- aminoethyl) glycine units. Unlike DNA or RNA in the unhybridized state (single strand) which can adopt a helical structure through base-stacking, although highly flexible, PNA does not have a well-defined conformational folding in solution. Herein, we show that a simple backbone modification at the γ-position of the N-(2-aminoethyl) glycine unit can transform a randomly folded PNA into a helical structure. Spectroscopic studies showed that helical induction occurs in the C- to N-terminal direction and is sterically driven. This finding has important implication not only on the future design of nucleic acid mimics but also on the design of novel materials, where molecular organization and efficient electronic coupling are desired.
Introduction
Biotechnology applications, for the most part, are developed on the basis of the ability of specific substrates to bind to cellular targets. Such binding would either interfere with the physiological function of the targets and/or elicit the reporter signals. Establishing high binding affinity and selectivity between the substrates and the targets is crucial to the success of many of these applications. One way to achieve this goal would be to preorganize the substrates into the binding conformation prior to complexation. This would minimize the entropic penalty associated with most molecular recognition events and increase the rigidity of the substratessthereby providing both stability and selectivity.1 While this concept has been successfully applied to the design of small molecules for guest-host recognition,2 it has been less successful with the design of larger and more flexible oligomeric molecules such as peptides and nucleic acids and their synthetic mimics, due to the large degree of freedoms although some progress has been made.3-9 In this article we show that a simple γ-backbone modification can transform a randomly folded peptide nucleic acid (PNA) into a right-handed helix. These conformationally preorganized helical PNAs bind to DNA and RNA with exceptionally high affinity and sequence selectivity.
PNA is a synthetic analogue of DNA and RNA, developed more than a decade ago, in which the naturally occurring sugar phosphate backbone has been replaced by the N-(2-aminoethyl) glycine units, Scheme 1.10 PNA can hybridize to complementary DNA or RNA strand through Watson-Crick base-pairing; because of the unnatural backbone, PNA can neither be recognized nor easily degraded by proteases or nucleasessall of which make PNA an attractive reagent for biotechnology applications.11 However, unlike DNA or RNA in the unhybridized state (single strand) whose structure, to a large degree, is extended in solution due to the negatively charged phosphate backbone, PNA tends to fold into complex globular structures, 12,13 presumably due to the collapse of the hydrophobic nucleobases. In fact, this conformational collapse has been exploited in the development of stemless PNA molecular beacons, taking advantage of the proximity between the two termini in the unhybridized state.12,14-16 Several modifications have been made to the PNA N-(2-aminoethyl) glycine backbone in attempts to increase its rigidity;17,18 however, only a few such modifications showed improvements in the hybridization properties19-24 many of which require either elaborate
, PNA and Gamma PNA.PNG)
synthesis19-22 or the use of relatively expensive D-amino acids as starting materials.23,24 Of the various backbone modifications that have been made, only a few were made at the γ-position.25-27 A systematic study correlating structure with function at this position has not yet been established. To fill this void, we have developed a research program to explore the structural effects of γ-backbone modifications on the conformation and hybridization properties of PNA.
Click on PDF to read more regarding gamma PNA