ADVANCED QUANTUM CHEMICAL CALCULATION METHODS
The future’s bright
Dr Roland Lindh details his research into advanced quantum chemical calculation methods for
the study of chemical reactions, which could transform the landscape of chemical research
Moreover, the method can be applied to any
known or even unknown chemical compound
or reaction. The significance of the method
is that it allows the chemist to understand
chemical reactivity and the chemical bond from
the perspective of the so-called ‘molecular
orbital picture’. Today, this is used not only to
analyse the data from chemical experiments,
but also enables the computational chemist
to design new chemical compounds with
requested properties or chemical reactions that
are energy efficient and do not produce harmful
side products. A good example of the use of
computational chemistry can be observed
within the current studies of the chemistry of
radioactive waste products. Here, computer
simulations can be used to understand how we
clean up the mess without exposing humans or
the environment to any danger.
Could you provide an overview of the overall
objectives of your research?
The research we are conducting in our group
in Uppsala is, to a large extent, a continuation
of the pioneering work of two Swedish
groups led by Professors P O Löwdin, Uppsala
University, and B O Roos, Lund University.
Both are international giants in their own
respect in the field of establishing and
developing quantum chemical calculation
methods. We are following two main
objectives: first, to develop the technology
further to enable the approach to be
applied to larger molecular systems and to
simultaneously improve the accuracy of the
methods; second, to apply the methods to
chemical systems of significance both to
society and within the chemical community.
How powerful is this tool of computational
chemistry in understanding chemical
processes?
The method applies to any type of chemistry,
eg. physical chemistry, inorganic chemistry,
analytic chemistry, biochemistry, catalysis, etc.
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INTERNATIONAL INNOVATION
How has the applicability of CASPT2 and
CASSCF methods enabled the study of
photo chemical processes on large realistic
model systems?
The photo chemical processes are a
manifestation of the quantisation of the
electronic states of a molecule. In the photo
chemical processes a molecular system is
thrusted from one electronic state to a second
state by the interaction with a photon. Once
in the new state the molecular system evolves
to find a new structure particular to that new
state, or might descend to yet a third state.
Most quantum chemical methods can only
explicitly handle one state at a time. However,
the CASPT2 and CASSCF models are designed
to handle several states at the same time,
rendering them perfect for studies of photo
chemical processes. With the augmentation of
the Cholesky Decomposition we can now also
apply the method to molecular systems of the
same size as those which experimentalists use.
What progress have you made in your
investigations into chemiluminescence and
bioluminescence? What is the primary goal
of this research?
The primary goal of this research is to
understand the prerequisites for a thermal
chemical reaction yielding products that are
in an electronically excited state. That is,
to understand the significance of Nature’s
design of the so-called luciferin molecules.
The secondary goal is to understand how
this molecule interacts with its associated
enzyme: the luciferase system. Over the
last four years we have gained significant
insight into this for the luciferin-luciferase
system of the firefly beetle, and our next
goal is to proceed with similar studies on
other luciferin molecules – for example, the
coelenterazine substrate. The ultimate goal,
of course, is to learn from Nature and to
make artificially designed luciferin molecules
tailored to meet our needs.
Why have you chosen to study the luciferinluciferase system of firefly beetles? Were
there any other potential candidates, and
what application could knowledge of the
systems of bioluminescence have?
The reason is simple: the luciferin molecule
of the firefly beetle is the smallest known.
The size of the molecular system could be a
bottleneck in our simulations; with the firefly
beetle luciferin we have no such problem. There
are other potential candidates. We are now
looking at a much larger luciferin molecule:
the coelenterazine molecule. Although this
molecule is (in terms of chemical composition)
a very different system as compared to
the firefly luciferin, it carries the very same
chemical functionality. Right now, we are not
looking at any specific applications, but I can
literally see a bright future for these reactions
as they convert chemical energy into light
under high efficiency, cold light. However,
today the technique is already in use as a
biochemical marker in pharmaceutical research.
ADVANCED QUANTUM CHEMICAL CALCULATION METHODS
Molecular illumination
A team of scientists from across the globe have been developing and
improving techniques within their studies of computational chemistry
COMPUTATIONAL CHEMISTRY IS a powerful
tool that enables scientists to model molecular
systems and compute the electronic wave
function. In many respects, one can compare
the method with the computer tools used in
the industrial design of cars or planes known as
Computer-Aided Design and Computer-Aided
Manufacturing (CAD-CAM). However, where the
car industry may look to optimise properties such
as favourable drag to reduce fuel consumption,
the computational scientist aims to understand
chemical reactions. Standard CAD-CAM
techniques involve classic Newtonian mechanics,
whereas the process of observing and describing
molecular systems requires quantum mechanics
to ensure that findings are qualitatively and
quantitatively correct. With the latter methods
scientists are able to study all aspects of a chemical
process, whether known or unknown, and thus
understand how they may be manipulated, either
to create new compounds with novel properties,
or ascertain how alternative chemical reactions
(green chemistry) may be used to replace current
wasteful approaches. Professor Roland Lindh,
Chair of the Theoretical Chemistry Program at the
Department of Chemistry – Ångström, Uppsala
University, Sweden, has been involved in two major
research projects seeking to take advantage of the
large development potential of computational
chemistry to enable the study of larger molecular
systems, standing us in better stead to develop the
chemistry of the future.
composition and structure, and to select some of
the quantum chemical methods that are available.
The program then assists the computational
chemist in finding stable molecular structures,
reactions energetics, and enables them to study
how the molecule is perturbed by external
influences such as changes in geometry or external
electric fields. Depending on the problem studied,
this process can take anything from a few minutes
to several days or even weeks.
REDISCOVERY
The Cholesky Decomposition technique for
two-electron integrals, first introduced in 1977
but mostly overlooked since then, is a method
that significantly reduces both the computation
time and the size of the data without significant
loss of accuracy, as Lindh explains: “In some
senses, it can be compared with the methods
for digital picture compression, for example
the JPEG technique”. Due to this reduction the
Cholesky Decomposition enables the computer
implementation of quantum chemical methods
to be much faster. Within the MOLCAS package
Lindh and his team have rediscovered the abilities
MOLCAS
All computational chemical methods require a
description of the interaction between electrons.
To attain this, it is necessary to compute the twoelectron integrals that describe these interactions.
The generation and processing of these integrals –
and their manipulation in the computer programs –
represents a major bottleneck in such calculations.
The MOLCAS quantum chemistry program
package, developed by many computational
chemists over the last 20 years, allows the user to
simulate the properties of any chemical system on
a computer. The user needs to know the molecular
FIGURE 1. The CASPT2 method, a unique general
purpose theoretical method applicable to a number of
experimental phenomena.
of the Cholesky technique and used it in stateof-the-art simulations: “We have over the last
few years refined this method and demonstrated
that it can be used in most quantum chemical
methods for energy and structure studies”. As a
result of this development, it is now possible to
employ the method with any type of standard
wave function models such as Complete Active
Space Self-Consistent Field (CASSCF) and
multi-configurational reference second order
perturbation theory (CASPT2). The approach
can be used for molecular systems that are four
to five times larger than previously possible, and
Lindh is keen to explain the significance of this: “It
allows for application to real systems rather than
smaller model systems. Today the methods can
be applied to systems of the size of 100 atoms;
in the past, anything larger than 20 would have
been prohibitive”. This extension to much larger
systems has enabled in particular the study of
photo chemical processes on large realistic model
systems. “I personally have been using this new
ability in my own research on the phenomena of
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INTELLIGENCE
ADVANCED QUANTUM CHEMICAL
CALCULATION METHODS FOR STUDIES
OF CHEMICAL REACTIONS
OBJECTIVES
• The development of Cholesky Decomposition
methods to speed up the treatment of the socalled two-electron integrals (aka electronrepulsion integrals) in ab initio theory
• The understanding of the bioluminescence
of luciferin at the molecular orbital level of
theory
PARTNERS
University of Marseilles, France • Beijing
Normal University, China • University of the
Witwatersrand, Johannesburg, South Africa •
University of Oslo, Norway
KEY COLLABORATORS
Dr Nicolas Ferré • Professor Yajun Liu • Dr
Isabelle Navizet • Dr Thomas B Pedersen
FUNDING
The Swedish Research Council • National
Nature Science Foundation of China • Major
State Basic Research Development Programs
• Fundamental Research Funds for the Central
Universities • The French National Center for
Scientific Research • DST/NRF South African
Research Chairs Initiative • The Research
Council of Norway
CONTACT
Dr Roland Lindh
Project Coordinator
Department of Chemistry – Ångström
Uppsala University
751 20 Uppsala, Sweden
T +46 18 471 3263
E [email protected]
chemiluminescence – without it, my work would
not have been possible,” Lindh reflects.
CHEMILUMINESCENCE
Chemiluminescence is defined as a chemical
reaction that yields a light-emitting product,
and bioluminescence denotes the same process
as demonstrated within a living organism. The
most well-known bioluminescence may be
observed in the firefly beetle, and for this reason
it was chosen as the basis of initial studies. In this
organism, an enzyme, luciferase, controls the
chemiluminescent reaction. One of the key steps
in the bioluminescent reaction is the thermallyactivated fragmentation of a peroxide bond
ejecting a CO2 molecule and a remaining fragment
which is in an excited state. The excitation energy
is released as an emission of a photon. However,
this reaction normally requires too much energy
to take place naturally in living organisms.
Further investigation of this process revealed
that the breaking of the peroxide bond is the clue
to understanding the anomalies. This realisation
lead to a study of the Charge Transfer Induced
Luminescence, (CTIL) mechanism. Nature has
solved the energy discrepancy by positioning an
aromatic system with promiscuous electrons
next to the peroxide bond. During the peroxide
bond fragmentation, the aromatic system lends
an electron to the fragmenting bond which
significantly lowers the energy needed for the
bond breaking. Upon completion of the process
the electron is donated back, thus completing
the CTIL mechanism.
DR ROLAND LINDH gained his PhD in
Theoretical Chemistry from Lund University,
Sweden, in 1988, and completed his
postdoctorate studies at IBM Alamaden
Research Center, San Jose, CA, USA, in 1991.
Between 1991-2010 he was a researcher at
the Department of Theoretical Chemistry at
Lund University. He is now Chair and Professor
of the Theoretical Chemistry programme at
the Department of Chemistry – Ångström,
Uppsala University, Sweden.
INTERNATIONAL INNOVATION
This research into bioluminescence is now
developing into studies of other types of
luciferin molecules such as coelenterazine, a
luciferin molecule found in jellyfish, amongst
other organisms. Initial studies are delivering
some interesting results. At first, the team
thought this system was very different from
the luciferin molecule of the firefly beetle, but
on closer inspection, similarities were identified
with respect to the chemical functionality
of the various parts of the molecule, such as
the peroxide unit, CTIL promoting fragments,
protonation/deprotonation controlling groups
and tethers. It is very exciting to see that Nature
Today the methods can be applied
to systems of the size of 100 atoms;
in the past, anything larger than 20
would have been prohibitive
has used different molecular frameworks
to solve the same functional problem. The
current project on the coelenterzine molecule
will deal with the difference between the
fluorescent and chemiluminescent states of
this system to discern why they are not the
same. This fact has implications on what kind
of experimental procedures can be used to
study the bioluminescent process, and while
the impact of the technology in everyday life
is still in the early stages, in medical research,
bioluminescence is already being used to probe
the onset of specific genes.
CONTINUED COLLABORATION
FIGURE 2. The molecular orbital understanding of the
luciferin molecule (centre molecule), the molecule at
the core of the understanding of bioluminescence, was
derived in a series of studies on smaller model systems
up to the full luciferin molecule in the associated
enzyme, luciferase.
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NEW DISCOVERIES
As with many theoretical chemistry research
projects, these studies have represented a
truly international endeavour with significant
contributions from partners from the universities
of Marseille, France; Beijing, China; and
Johannesburg, South Africa. The different centres
have shared knowledge and have effectively
designed their individual studies to complement
one another in a drive to understand the bigger
picture. Lindh appreciates the input made from
across the consortium: “I am very happy and
pleased with this collaboration in all aspects,
and we owe much of the success of the project
to our partners”.