Non covalent interactions are incredibly important characteristics in supermolecular chemistry, especially in biological molecules, such as nucleic acids and enzymes. These can include pi-pi, pi-cation and electrostatic interactions. Contributed by: Alexandra Kent & Allyson Brome (Undergraduate Students) University of Utah 2014

1. Organic Pedagogical Electronic
Network
Non-Covalent Interactions
Alexandra Kent & Allyson Brome
University of Utah

2. Non Covalent Interactions
Wiki Page: http://en.wikipedia.org/wiki/Non-covalent_interactions
Other References: Anslyn, E. V., Dougherty, D. A. (2006). Modern Physical Organic Chemistry. Sausalito, CA. University Science.
Overview:
Non covalent interactions are incredibly important characteristics in supermolecular
chemistry, especially in biological molecules, such as nucleic acids and enzymes.
These can include pi-pi, pi-cation and electrostatic interactions.
Pi-Pi Interactions
Pi-Pi interactions in benzene can be
observed in three different ways.
These occur when pi orbitals overlap in
favorable orientations.
Cation-Pi Interactions
Cation-pi interactions are a strong
interaction between electrons from
the pi system and a cation. These
interactions have the potential to
be as strong or stronger than H-
bonding. They are detected by a
large upfield shift in the H-NMR
spectra, because the protons are
shielded by the pi system.

3. Examples
DNA Helix
Pi stacking interactions are
incredibly important in the
stabilization of a DNA double helix.
The nucleobase stacking can even
influence the interstrand hydrogen
bonding that glues together the
helical structure.

4. Examples
G-quadruplex
G-quadruplex architecture is
a more complex example
that incorporates cation-pi
as well pi stacking
interactions. These can be
used for biosensing
applications.
Wiki Page: http://en.wikipedia.org/wiki/G-quadruplex
Other References: Matta, C. F.; Castillo, N.; Boyd, R.; J. Phys. Chem. 2006, 110, 563-578

5. Molecular Tweezers
References: Landon P. B.; Ramachandran, S.; Gillman, A.; Gidron, T; Yoon, D.; Lal, R.; Langmuir, 2012, 28, 53-
540
One of the more interesting biological examples uses the non covalent interactions in nucleic
acids for non traditional applications. Molecular Tweezers are short sequences of DNA that can
be used as a renewable system of detection for DNA sequences. They can be integrated with
DNA nanomachines for lab-on-a-chip utilization.
Molecular tweezers utilize the additive properties
of intermolecular forces. Inosine, a guanine
analogue, is present in the red part of the original
sequence above. Therefore, in the presence of the
complementary blue strand, the tweezers open
because binding of the blue strand is favored over
the inosine mutated red strand. However, this blue
strand has a base overhang. In accordance with
the additive nature of intermolecular forces, the
addition of a complementary sequence that can
bind to that overhang will displace the blue
sequence, closing the tweezers.
This opening and closing
event can be detected
using a fluorophore-
quencher pair. This
process, as shown by the
data on the left, is
regenerative and the
tweezers can be used
multiple times.

6. Problems
Wiki Page: http://en.wikipedia.org/wiki/Ethidium_bromide
Other References: Zhang, L.; Peritz, A.; Meggers, E. J. Am. Chem. Soc. 2005, 127, 4174-4175; Haeusler et. al, Nature, 2013, 507, 195-200
1. In DNA it is a well known fact that the sugar
phosphate backbone contributes some stability to
the alpha-helical structure. However, it has been
shown that this sugar phosphate backbone can be
replaced with a glycol backbone, and this GNA
molecule maintains a helical structure. Propose an
explanation for this phenomena.
2. Water is a known fluorescence quencher.
Ethidium bromide is non-fluorescent in aqueous
solution, but upon the addition of double stranded
DNA, small fluorescence is observed. What is
occurring to cause the fluorescence?
3. The DNA sequence, (GGGGCC)4 will naturally
form a hairpin loop, however in the presence of KCl
it can form a G-quadruplex structure. Why does
this occur?

7. Solutions
1. This is observed because the helical structure is mainly stabilized through pi-
stacking and hydrogen bonding interactions of the base pairs, despite the added
stability of the sugar phosphate backbone.
2. The ethidium bromide is intercalating into the DNA strand which is a
more hydrophobic environment. This causes it to shed the water
molecules, allowing it to fluoresce.
3. This structure is stabilized by the KCl because the K+ is favorably
interacting with the pi system, which favors the g-quadruplex structure more
so than the hairpin loop.

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Contributed by:
Alexandra Kent & Allyson Brome (Undergraduate Students)
University of Utah
2014