NOBEL PRIZE IN CHEMISTRY 2013
The Nobel Prize in
Chemistry 2013 was awarded jointly to Martin Karplus, Michael Levitt and Arieh
Warshel "for the development of multi scale models for complex
chemical systems".
Background
Chemistry and
Biochemistry have developed very rapidly during the last 50 years. This applies
to all parts of the fields, but the development of Biochemistry is perhaps the
most striking one. In the first half of these 50 years the determination of
protein structure was perhaps the field where the largest efforts were spent
and the largest progress was made. The standard methods to analyse the
structure of proteins are X-ray crystallography of crystals or analysing the
spin –spin couplings obtained from NMR-spectroscopy. What is perhaps less well
known is that in the computer programs that are used to analyse the diffraction
pattern from an X-ray investigation or the spin-spin couplings obtained from a
NMR experiment there is hidden a computer code that calculates the energy of
the considered structure based on empirically and theoretically obtained
potentials describing the interaction between the atoms in the system. The
reason for this is that there is not enough experimental information to
uniquely determine the structure of the studied system. This is just one of the
aspects of how computers and theoretical models have become essential tools for
the experimental chemist.
Today the focus of
chemical research is much more on function than on structure. Chemists asks
questions like “How does this happen?” rather than “What does this look like?”
. Question about function are generally difficult to answer using experimental
techniques. Isotope labelling and femto second spectroscopy can give clues, but
rarely produce conclusive evidence for a given mechanism in systems with the
complexity characterizing many catalytic chemical processes and almost all
biochemical processes. This makes theoretical modelling an important tool as a
complement to the experimental techniques. Chemical processes are characterized
by a transition state, a configuration with the lowest possible (free) energy
that links the product(s) with the reactant(s). This state is normally not
experimentally accessible, but there are theoretical methods to search for such
structures. Consequently theory is a necessary complement to experiment.
The work awarded this
year´s Nobel Prize in Chemistry focuses on the development of methods using
both classical and quantum mechanical theory and that are used to model large
complex chemical systems and reactions. In the quantum chemical model the
electrons and the atomic nuclei are the particles of interest. In the classical
models atoms or group of atoms are the particles that are described. The
classical models contain much fewer degrees of freedom and they are
consequently evaluated much faster on a computer. Further more, the physics
that is 3 (9) used to describe the
classical particles is much simpler and this also contributes to speeding up
the modelling on a computer. This year´s
laureates have shown how to develop models that describe part of a system using
first principle, quantum chemical models for a central part of the system and
how to link this part to a surrounding, which is modelled using classical
particles (atoms or group of atoms). The key accomplishment was to show how the
two regions in the modelled system can be made to interact in a physically
meaningful way. Frequently the entire molecular
system is embedded in a dielectric continuum. A cartoon of a typical system is
shown in Figure 1.
Historical
perspective
Theoretical modelling
as described above restson basically four different types of development. The
central region in the system, the space filling atoms(red and gray), is
described using a Quantum Chemical method2. Walter Kohn and John Pople were
awarded the Nobel Prize in Chemistry 1998 for the development of such
methods. The development of Quantum Mechanics3,
which the Quantum Chemistry rests on is almost 75 years older and was the basis
for five different Nobel Prizes in Physics from 1918 –1933. The laureates were
M. Planck in 1918, N. Bohr in1922, Prince de Broglie in 1929, W. Heisenberg in
1932, and E. Schrödinger and P. Dirac in1933.
The theory used for the
modelling of the surrounding molecular system consists of several pieces. First
of all a model is needed to describe the intra molecular potential for these
molecules. The model that is used today originates from 1946, when three groups4-6independently
suggested such a model, based on Coulomb and van der Waals (van der Waals was
awarded the Nobel Prize in Physics 1910) interactions. F.H. Westheimers group
soon became leading in this field. In those days computers did not exist. N.
Allinger developed computer code and used computers to optimize the structure
of molecules using such classical,empirical potentials in a set of molecular
mechanics methods7called MM1, MM2 and so on. In these methods the energy of the
system was minimized to obtain the structure of the studied system. The
MM-methods were primarily used for systems built from organic molecules.
In a parallel line of
development G. Némety and H. Scheraga8used the ideas of Westheimer and Allinger
and developed simplified versions of their potentials for the use in
statistical mechanics simulations and for energy minimisation of protein
structures. Roughly at this time quantum chemical methods started be used for the
construction of inter-and intra-molecular potentials for complex systems.
Leading persons in this field were S. Lifson and A. Warshel with the
development of the Consistent Force Field (CFF) method9. M. Levitt and S.
Lifson were the first to use such potentials to minimize the energy of a
protein10. Another well-known example of a theoretically constructed potential
was the so-called MCY11potential for the water –water interaction. This
potential was based entirely on quantum chemical calculations that were used to
create a classical potential with terms describing electrostatic and van der
Waals interactions.
The advantage of the
classical potential-based methods is that the energy can easily be evaluated
and large systems can be studied. The drawback is that they can only be used
for structures where the interacting molecules are weakly perturbed.
Consequently they cannot be used for the study of chemical reactions where new
molecules are formed from the reactants.
Conversely, quantum
chemical methods can be used for the study of chemical reactions where
molecules are formed and destroyed, but they are very demanding with respect to
computer time and storage and only smaller systems can be handled.
Given that the problem
with the potential functions describing the surrounding is solved, the problem
of deciding the proper conformation(s) for the surrounding remains. There are
two different approaches to this problem, the one used by Allinger in his MMX
methods, to minimize the energy of the system and generate one characteristic
conformation, and that used by Némety and Scheraga,to use statistical mechanics
methods, like Molecular Dynamics (MD) 12or Monte Carlo (MC)12and generate many
configurations with a correct (in principle) statistic weight.
The importance of the
work of the laureates is independent of what strategy is used for the choice of
studied configuration(s).The prize focuses on how to evaluate the variation in
the energy of the real system in a accurate and efficient way for systems where
relatively large geometry changes or changes in electronic configuration in a
smaller part of the studied system is strongly coupled to a surrounding that is
only weakly perturbed. One way to address this problem is to develop an efficient
computer code based on the Schrödinger equation that makes it possible to
handle systems of the size that is required. The Car –Parinello approach13is
the leading strategy along this line. It is however still too demanding with
respect to computer resources to be able to handle the large systems necessary
for bio-molecular modelling or extended supra-molecular systems with the
required accuracy. The solution to the problem is instead to combine classical
modelling of the larger surrounding, along the line suggested by Westheimer4,
Allinger7, Némety and Scheraga8, with quantum chemical modelling of the
coreregion, where the chemically interesting action takes place.
The
contributions of the three laureates
The first step in the
development of multi scale modelling was taken when Arieh Warshel came to visit
Martin Karplus at Harvard in the beginning of the 70’ies. Warshel had a
background in inter-and intra-molecular potentials and Karplus had the
necessary quantum chemical experience. Together they constructed a computer
program that could calculate the π-electron spectra and the vibration spectra
of a number of planar molecules with excellent results14. The basis for this
approach was that the effects of thσ-electrons and the nuclei were modelled
using a classical approach and that the π-electrons were modelled using a PPP15(Praiser
–Parr –Pople) quantum chemical approach corrected for nearest overlap. Figure 2
shows a typical molecule studied in that work
This was the first work
to show that it is possible to construct hybrid methods that combine the
advantages of classical and quantum methods to describe complex chemical
systems. This particular method is restricted to planar systems where symmetry
makes a natural separation between the π-electrons that were quantum chemically
described and the σ-electrons that were handled by the classical model, but
this is not a principal limitation, as was shown a few years later, in 1976,
when Arieh Warshel and Michel Levitt showed that it is possible to construct a
general scheme for a partitioning between electrons that are included int he
classical modelling and electrons that are explicitly described by a quantum
chemical model. This was made in their study of the “Dielectric, Electrostatic
and Steric Stabilisation of the Carbonium Ion in the Reaction of Lysosyme”16.
Several fundamental problems needed to be solved in order for such a procedure
to work. Energetic coupling terms that model the interaction between the
classical and the quantum system must be constructed, as well as couplings
between the classical and quantum parts of the system with the dielectric
surrounding. The studied system is shown in Figure 3.
In the time between the
publishing of the two publications referred to above(1975), an other important
step, which made it possible to study even larger systems, was taken by Michel
Levitt and Arieh Warshel in their study of the folding of the protein Bovine
Pancreas Trypsin Inhibitor (BPTI)17. The type of simplifications of the studied
system used in that study is illustrated in Figure 4.
In this work, the
folding of the protein from an open conformation to a folded conformation was
studied, and it was shown that it is possible to group atoms in a classical
system into rigid units and to treat these as classical pseudo atoms.
Obviously, this approach further speeds up the modelling of a system.
Multiscale
modelling today
The work behind this
year’s Nobel Prize has been the starting point for both further theoretical
developments of more accurate models and applied studies. Important
contributions have been given not only by this year’s laureates18-20but also by
many others including J. Gao21, F. Maceras and K. Morokuma22, U.C. Sing and P.
Kollman23and H. M. Senn and W. Thiel24. The methodology has been used to study
not only complex processes in organic chemistry and biochemistry, but also for
heterogeneous catalysis and theoretical calculation of the spectrum of
molecules dissolved in a liquid. But most importantly,it has opened up a
fruitful cooperation between theory and experiment that has made many otherwise
unsolvable problems solvable.
Martin
Karplus
Born: 15 March
1930, Vienna, Austria
Affiliation at the time
of the award: Université de Strasbourg, Strasbourg, France, Harvard
University, Cambridge, MA, USA
Prize motivation: "for
the development of multiscale models for complex chemical systems"
Michael
Levitt
Born: 9 May 1947,
Pretoria, South Africa
Affiliation at the time
of the award: Stanford University School of Medicine, Stanford, CA, USA
Prize motivation: "for
the development of multi scale models for complex chemical systems"
Arieh
Warshel
Born: 20 November
1940, Kibbutz Sde-Nahum, Israel
Affiliation at the time
of the award: University of Southern California, Los Angeles, CA, USA
Prize motivation: "for
the development of multi scale models for complex chemical systems"
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