PW_mar13_sample_issue

Quantum frontiers: Quantum biology
This could
provide
information
on how the
tunnelling
process is
affected within
the busy, warm
environment of
a living cell
44
1 Base-pair mutants
N
N
N
H
N
N
H O
O
adenine thymine
One of the two base pairs comprising DNA, the adenine–thymine pair
is joined together by two hydrogen bonds in the configuration shown,
known as the canonical structure. Occasionally, both hydrogen
nuclei (protons) in these bonds can switch allegiance and travel
along the dashed lines to be close to the opposite half of the base
pair, forming the tautomeric structure. Replication of the base pair
while in this form leads to an error in the genetic code – a mutation.
(Rev. Mod. Phys. 35 724). The protons spend most of
their time in their deeper wells, but can occasionally
tunnel across to the shallow well to form the tautomeric
structure. A mutation can then take place only
if the rarer tautomeric form remains stable during the
replication process. What could happen, for example,
is that an A–T base pair in DNA could turn into its
tautomeric form, A*–T*. Then, when the two strands
of DNA split, the tautomer of adenine will now bind
to cytosine (A*–C). This would cause an error in the
genetic code (because the new strand now has a C
replacing a T in its sequence) and hence a mutation.
Modelling mutation
Half a century on from Löwdin’s double-proton tunnelling
proposal, experiments by Lorena Beese and
colleagues at Duke University in the US in 2011 look
to have at least confirmed the hypothesis put forward
by Watson and Crick – that tautomeric forms of DNA
bases can cause mutations (Proc. Natl Acad. Sci. 108
17644). However, the mechanism by which canonical
base pairs become tautomeric remains unconfirmed.
Many computational chemistry groups around the
world have, over the past two decades, attempted to
model the process of double proton transfer in the
adenine–thymine base pair. (This base pair is chosen
because it is simpler to model than cytosine–guanine,
which is joined by three hydrogen bonds rather
than two.) In recent years, a method called density
functional theory (DFT) has emerged as the frontrunner
among the various computational methods
to model the structure of large molecules and manyatom
systems. In this approach, the properties of a
many-electron system can be determined accurately
by examining its electron density. DFT calculations
are carried out by large computer codes that have
become so sophisticated that non-aficionados can
use them essentially as black boxes into which one
feeds information about the system of interest (such
as a crystal or a protein). These codes have been
successfully used to tackle problems in material
science, condensed-matter physics, computational
H
N
N
physicsworld.com
chemistry and, more recently, nuclear structure and
molecular biology.
But even incorporating into the calculation the
behaviour and structure of hundreds of atoms that
make up a section of DNA is not likely to be sufficient
to produce a realistic model. Lone DNA is
an example of what is known as an “open” quantum
system, whereby the surrounding environment can
influence its behaviour. It is known, for example, that
in the case of 5-Bromouracil – a molecule similar
to adenine – the presence of water molecules completely
alters the shape of the double well, making
the rarer tautomeric form more energetically favourable
than the canonical one, suggesting that adenine
might be similarly affected inside the cell.
The approach being adopted by my PhD student,
Adam Godbeer, at the University of Surrey working
with theoretical chemists at University College
London, led by Michaelides, involves using DFT to
calculate very accurately the shape of the potential
energy surface by taking into account as much of the
structural information of the DNA base pair as possible,
constrained as always by numerical complexity
and computational power when dealing with manybody
systems. This static potential energy surface
is then used to calculate the time evolution of the
proton tunnelling process. An added complication is
the presence and influence of the external environment,
for this is an open quantum system where the
surrounding water molecules must also be taken into
account. This leads to what is called a decoherence,
or dissipative, term in the quantum-mechanical
equations, which could provide information on how
the tunnelling process is affected within the busy,
warm environment of a living cell.
In parallel with this theoretical work, an experiment
being conducted at Surrey, led by molecular
biologist Johnjoe McFadden, is also attempting to
pin down whether proton tunnelling plays a role in
tautomeric mutagenesis. The experiment involves
replacing the protons in the hydrogen bonds with
their more massive isotope, deuterons, and seeing if
the mutation rate changes when the heavier isotope
is present. This is done by replicating short strands
of DNA in deuterated water and using a powerful
technique called a polymerase chain reaction to produce
many copies of the strands very quickly. As the
double helix splits and each strand pairs up with a
new one made from the raw material available in its
surroundings, use is made of the deuterium in the
water for some of the hydrogen bonds. If quantum
tunnelling plays a role in mutagenesis we might
expect to see a drop in the mutation rate – since deuterons,
with twice the mass of protons, will tunnel
much more rarely.
Complicating factors
Unfortunately, I am learning that nothing is ever
that straightforward in biology and – although early
results point tentatively towards Löwdin’s proposal
being confirmed – a number of other quantum
nuclear effects must be taken into account. For example,
the heavier deuteron means that the vibrational
frequency of the chemical bond it forms is affected.
Physics World March 2013