||Researchers at the University
of Pennsylvania School of Medicine are the
first to observe and measure the internal motion inside
or its “dark energy.”
||This research has
revealed how the internal motion of proteins affects their
function and overturns the standard view of protein structure-function
relationships, suggesting why rational drug design has been
magnetic resonance spectroscopy, the investigators
were able to look at the changes in the internal motion
of calmodulin itself in each of the six different protein
binding situations. They found a direct correlation between
a change in calmodulin’s entropy – a component
of its stored energy – and the total entropy change
leading to the formation of the calmodulin-protein complex.
||The findings were published in the current
issue of Nature.
(PHILADELPHIA) – Researchers at the University
of Pennsylvania School of Medicine are the first
to observe and measure the internal motion inside proteins,
or its “dark energy.” This
research, appearing in the current issue of Nature, has
revealed how the internal motion of proteins affects their function
and overturns the standard view of protein structure-function relationships,
suggesting why rational drug design has been so difficult.
Artist rendering of calmodulin molecule depicting protein "dark energy."
Click on thumbnail
to view full-size image
“The situation is akin to the discussion in astrophysics in which
theoreticians predict that there is dark
matter, or energy, that no one
has yet seen,” says senior author A. Joshua
Wand, PhD, Benjamin
Rush Professor of Biochemistry. “Biological theoreticians have
been kicking around the idea that proteins have energy represented by
internal motion, but no one can see it. We figured out how to see it
and have begun to quantify the so-called ‘dark energy’ of
Proteins are malleable in shape and internal structure, which enables
them to twist and turn to bind with other proteins. “The motions
that we are looking at are very small, but very fast, on the time scale
of billions of movements per second,” explains Wand. “Proteins
just twitch and shake.” The internal motion represents a type of
energy called entropy.
Current models of protein structure and function used in research and
drug design often do not account for their non-static nature. “The
traditional model is almost a composite of all the different conformations
a protein could take,” says Wand.
The researchers measured a protein called calmodulin and its interactions
with six other proteins when bound to a protein partner one at a time.
These binding partners included proteins important in smooth
muscle contraction and a variety of brain functions.
magnetic resonance spectroscopy, the investigators were
able to look at the changes in the internal motion of calmodulin
itself in each of the six different protein binding situations. They
found a direct correlation between a change in calmodulin’s entropy – a
component of its stored energy – and the total entropy change leading
to the formation of the calmodulin-protein complex. Finding out
the contribution from individual proteins versus the entropy, or movement,
of the entire protein complex has been more difficult and has been overcome
in this study. From this individual contribution they deduced that changes
in the entropy of the protein are indeed important to the process of
calmodulin binding its partners.
“Before these unexpected results, most researchers in our field
would have predicted that entropy’s contribution to protein-protein
interactions would be zero or negligible,” says Wand. “But
now it’s clearly an important component of the total energy in
Because of this new information, the researchers suggest that the entropy
component may explain why drug design fails more often than it works.
Currently, drugs are designed generally based on the precise structures
of their biological targets, active regions on proteins that are intended
to inhibit key molecules. However, the number of designed molecules actually
binding to their targets is low for many engineered molecules. “We
think that this is because the design is based on a model of a static
protein, not the moving, hyper protein that is constantly changing shape,” say
Wand. “We need to figure out how this new information fits in and
perhaps drug design could be significantly improved.”
Future directions include understanding whether the principles revealed
by this study are universal and impact the thousands of protein-protein
interactions that underlie biology and disease. As Wand explains, “Protein-protein
interactions are central to ‘signalling’, which is often
the molecular origin of diseases. Cancer, diabetes, and asthma are three
important examples. We are currently looking at the role of protein entropy
in the control of critical signaling events in all three.”
This work was funded by grants from the National
Institute of Diabetes and Digestive and Kidney Diseases. Co-authors
on the study are Kendra
King Frederick, Michael S. Marlow, and Kathleen G. Valentine,
all from Penn.
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