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Development of Advanced QM/MM Techniques for Enzyme
Simulation |
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One of the primary
limitations of classical molecular dynamics simulations
is the inability to break covalent bonds during a
simulation. This prohibits the direct observation of
reaction events during a simulation. In addition
classical MD simulations require parameters for all
bonded and non-bonded interactions within the system.
Such parameterization is typically done for all amino
and nucleic acids but a significant number of chemically
interesting proteins employ co-enzymes and catalytic
metal centers which are typically not covered by
traditional protein force fields.
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We are developing
advanced, hybrid quantum mechanical/molecular mechanical
(QM/MM) techniques that offer a possible solution for
these limitations. Research in the lab currently focuses
on:
1)
Improvements in the accuracy of semi-empirical
Hamiltonians.
2) Links
between AMBER and ADF to support DFT based QM/MM
simulations.
3) Performance
and parallel scaling improvements to QM/MM MD
simulations.
4) Development
of techniques for allowing variable QM regions
during MD simulations.
5) Standalone
libraries for high performance semi empirical QM
calculations.
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Acceleration of Molecular Dynamics Simulations using
Graphics Processing Units |
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Modern GPUs offer a
substantial amount of untapped processing capability for
very little hardware or infrastructure cost.
In a joint
collaboration with
NVIDIA
the Walker Molecular Dynamics lab are developing GPU
accelerated versions of the major MD engines in the
AMBER
Molecular Dynamics Package. An initial version
supporting implicit solvent Generalized Born
calculations and explicit solvent Particle Mesh Ewald
simulations in the NVE, NVT or NPT ensembles was
released in April 2010 as part of the AMBER 11. Current
NVIDIA C2050 Tesla cards offer speedups of between 20
and 200x over a single Intel Nehalem core. (AMBER
on GPUs)
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Work is continuing to
further expand the set of features that are supported,
to improve performance further and to provide support
for acceleration across multiple GPUs within a single
node or across multiple nodes. |
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Development of Advanced Biofuels from Cellulosic Biomass |
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One of the biggest
challenges that mankind will have to face over the next
20 years is the transition from energy sources based on
fossil fuels to efficient carbon neutral renewable
energy technologies. There is no simple solution to this
problem and instead a plethora of methods will need to
be developed and employed. One promising technology is
the conversion of cellulosic plant matter into
bioethanol that can subsequently be used as a
replacement for gasoline.
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Image courtesy of the
National
Renewable Energy Laboratory |
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In collaboration with
the National Renewable Energy Laboratory, Cornell
University and the University of Michigan and funded by
the Department of Energy Scientific Discovery through
Advanced Computing (SciDAC) program we are developing
advanced techniques for studying the enzymatic
degradation of cellulose as part of research to improve
the efficiency of bioethanol production. |
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A
Comprehensive Phospholipid Membrane Force Field |
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Phospholipids serve
a major function in the cells of all organisms forming
the cell membranes of all living things. Increasingly
more and more is being learnt about the structure and
function of membrane bound proteins and yet there exists
only minimal classical force field support for phospholipid membranes.
In collaboration with
Prof Knut Teigen at the University of Bergen, Norway, we
are developing the next generation of phospholipid force
fields for MD simulations. The are being designed in
such a way that any combination of phospholipid membrane
can be built and simulated. We hope to release this soon
as part of the AMBER force field suite. |
Image of a membrane sandwiched
graphene structure courtesy of Petr Kral (See
here for more details) |
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Predicting Enzyme Activation Pathways |
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Traditionally drug
discovery has focused on finding ligands that bind to
enzyme active sites and inhibit their reactivity.
However, there exists plethora of alternative approaches
that seek to inhibit enzyme activation.
One such
example
is
the Adenovirus protease enzyme which is common to a
number of viruses including those responsible for avian
and swine flu. As part of the final stage of virus
replication the virus must remove the chemical
scaffolding that was constructed as part of the
replication process in order to break out of the host
cell and infect new cells. This is achieved by the
adenovirus protease enzyme which is initially
synthesized by the virus in an inactive form and must
then undergo an elaborate activation process. Hence the
development of drugs to inhibit this pathway is a major
research aim.
We are developing both
the methods, such as the Nudged Elastic Band (NEB)
approach, and applying these, in collaboration with
Brookhaven National Laboratory, to determine the
activation pathways and possible inhibition sites for
the Adenovirus Protease. This work is uncovering
intermediate states along the adenovirus activation
pathway that could ultimately lead to the development of
an entirely new class of antiviral drugs. |
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