Summary of Current Research - Dr Jamie Platts
The research carried out in my group centres around the use of ab initio and
density functional theory (DFT) calculations, along with analysis of the resulting charge
density distributions, to study and interpet a wide range of chemical phenomena. Much
recent effort has gone into the study of intermolecular interactions, but we are
interested in using similar methods to evaluate bonding and reactivity in a wide range of
organic, inorganic, and biological systems.
1) Non-covalent interactions
In recent years, we have focussed on developing and testing methods to study non-
covalent interactions such as hydrogen bonding and stacking, with particular interest
in their importance for the structure of biological molecules and drug-receptor interactions.
Ab initio methods such as MP2 and CCSD(T) give excellent accuracy for many
such interactions, but in their conventional form cannot be applied to systems containing
more than a handful of atoms. We have shown how use of local correlation methods such
as local MP2 (LMP2) can reduce the computational cost of these methods without loss of
accuracy for description of non-covalent interactions. The example below shows how this
LMP2 approach accurately reproduces the potential energy surface for a stacked benzene dimer.
Since demonstrating the potential of this approach for model systems, we have applied it
to a wide range of biologically important phenomena. The stacking of co-parallel bases in
DNA and RNA is one such example: the efficiency of the LMP2 approach allowed us to evaluate
benchmark ab initio interaction energies for different base-pair steps, against
which more approximate methods could be tested. We have also used the same methods to
predict the binding of intercalators, an important class of anti-cancer drug, to DNA,
highlighting the structural and energetic properties that affect binding. A typical
intercalator, ethidium bromide, bound to a base pair step, is shown below.
As well as accurate ab initio methods, we are interested in applying faster,
more approximate methods to study of non-covalent interactions, in order to further extend
the size of molecules or cluster that may be treated. Conventional density functional theory
(DFT) performs poorly for many non-covalent interactions, for example failing to predict any
binding whatsoever between stacked systems. In recent years we have shown how judicious choice
of the parameters of hybrid DFT can give surprisingly accurate predictions of the geometry
and energy of molecules and clusters bound by non-covalent interactions. In particular, Becke's
half-and-half functional reproduces interaction energies and potential energy surfaces for a
wide range of stacked molecules.
Much of this work has concentrated on DNA and its interactions with metal based anti-cancer drugs
such as cisplatin. These bind covalently to nucleophilic sites within the DNA chain, with complementary
non-covalent interactions in many cases. This binding disrupts the classical double-helix
structure of DNA to such an extent that repair proteins induce programmed cell death, or
apoptosis. A suitable theoretical description of this drug-receptor interaction must therefore
properly describe both the metal-DNA covalent and non-covalent bonding, and the internal
non-covalent interactions within DNA itself. An example of cisplatin binding to two guanine
bases is shown below.
Although DFT is rather computationally efficient, the size of representative portions of DNA
means that one cannot hope to model an entire double helix, along with associated counterions
and solvent, interacting with such a drug. In this case, we turn to hybrid quantum mechanics/
molecular mechanics (QM/MM) methods, in which only a small part of the entire system is
treated with a quantum mechanical method such as DFT, with the remainder approximated by a
much faster, classical approach. Appropriate classical approaches such as AMBER and CHARMM
are well-validated for nucleic acids, and allow efficient simulation of much larger DNA
fragments than would be possible otherwise. A typical set-up of a QM/MM calculation for
cisplatin interacting with DNA is shown below, with the QM region in bold and MM region
wireframe.
Platinum is not the only metal of interest in this field; recent work by the group of Peter
Sadler has shown that ruthenium-arene complexes show a great deal of promise as potential
anti-cancer agents. They also bind to DNA through a combination of covalent and non-covalent
interactions, but here the non-covalent part is rationally designed to induce greater
disruption through stacking interactions with DNA bases. DFT optimised geometry of one such
adduct, showing the co-planar orientation of arene ligand with DNA base, is shown below.
As well as these structural and energetics studies, I maintain an interest in using quantum
mechanical calculations coupled with statistical methods to predict
solvation properties. For instance, we have measured the permeability of around
40 organic and drug compounds through membranes consisting of 2% dioleyl-
phosphatidylcholine (DOPC) in dodecane, which is widely used as a screen for in vivo
cell and intestinal permeability. Using the inherent pH dependence of this permeability
(see below, left), we were able to calculate the "inherent" permeability of each
compound, which was then modelled using the established statistical methods. As a result,
we now not only have a predictive model suitable for virtual screening of new compounds,
but also physical insight into the molecular properties that inhibit or promote membrane
permeation (below, right).
Much of this work is currently also applied to the field of metal-based anti-cancer drugs.
Many methods and algorithms have been published to predict the solvation properties (
i.e. solubility, lipophilicity, absorption) of organic drugs, but methods for inorganic
drugs lag some way behind. We have developed methods to predict such properties from DFT
and/or semi-empirical calculations, for instance taking into account the exposed surface
area of different groups in a metal complex. We have reported quantitative structure-property
relation (QSPR) methods for a range of solvation properties of platinum drugs, including
both Pt(II) and Pt(IV) complexes, and this work continues.
Another area where non-covalent interactions play a vital role is catalysis, where subtle
differences in weak interactions can be amplified into very large differences in the outcome
of reaction. Working closely with Dr. Nick Tomkinson, we have studied in detail the catalytic
cycle involved in "organocatalysis", i.e. reactions catalysed by organic species.
We have calculated barriers to reaction for key steps within this cycle, and shown that these
are in excellent agreement with experimental data. We have also developed methods to rapidly
estimate catalytic yields and stereochemical outcomes based on relatively simple DFT calculations,
thereby avoiding the need to re-calculate the entire energy profile for each new proposed
catalyst.
2) Bonding and reactivity from the Electron Density
In addition to the rather applied problems described above, I have long-standing interests in
studying a variety of chemical bonding and reactivity problems using theoretical methods. In this,
we make extensive use of Bader's theory of
Quantum Theory of Atoms in Molecules (QTAIM). Much of this work is carried out in collaboration
with crystallographers such as Assoc. Prof. David Hibbs (Sydney) and Dr. Jacob Overgaard (Aarhus),
who are able to measure the same properties that our calculations predict. Systems of interest vary
from biologically relevant molecules such as the neurotransmitter taurine to novel inorganic species
such as subvalent,low-coordinate group 13 and 15 compounds. The latter are carried out as part of a
collaboration with Prof. Cameron Jones (Monash).
Recent highlights include the first characterisation of a non-nuclear maximum in the electron density
in a molecule, namely a Mg(I)-Mg(I) dimer. This highly unusual feature has been predicted for
body-centred cubic alkali and alkaline earth metals, but its presence in a stable molecule is
unprecedented and remarkable. The non-nuclear maximum is observed in both experimental and calculated
electron density, and is not an artefact of DFT or multipole methods employed to construct these
densities. The presence of this maximum also gives rise to a large area of charge concentration, or
negative Laplacian of the density, within the Mg-Mg bond, as shown below.
In another, we compared a number of density-based properties for the important
neurotransmitter taurine, a zwitterionic compound containing a sulphonic acid group. It
was found that hydrogen bonding interactions in the crystal significantly deform the
bonding in taurine compared to the free gas-phase molecule, results which may be important
for the interactions between taurine and lipids, receptors, and other biomolecules in the
condensed phase. The electrostatic potential around taurine is shown below.
