Protein Folding and Particle Accelerators: A New Solution

Protein Folding and Particle Accelerators: A New Solution


Water is fundamental to all life. Digestion, brain chemistry, drug metabolism… Almost all biology, even if you can’t see
it, has to take place in water. It’s the most important liquid of life. So most of the time when people think about
water they think about it as this magical substance where biology happens. It isn’t until quite recently that we really
paid attention to what water is doing in biology on the atomic scale where everything is actually
happening. Hi, my name is Sylvia, I run a research group
at the University of Oxford in the Dept of Biochemistry, where we’re trying to understand how water
interacts with the processes of life. What we’re looking at is the structure of
molecules in solution. Biomolecules, things like proteins or DNA,
but importantly we’re looking at thow the structure of molecules are hydrated by water
in solution. The difficulty with understanding water, especially
in solution and at the atomic scale, is it’s difficult to measure by most techniques. In many techniques the water itself is invisible. If you take a protein as an example, pretty
much every organism has proteins. They’re the ‘working horses’ in our bodies.
DNA code gives the blueprint to make protein. Proteins are made from very long chains of
building blocks which we call amino acids, which fold up into these complex three-dimensional
structures in order to function. All of this for the most part takes place
in solution. More interestingly, it has to fold in exactly the right way or it won’t
work. And I mean exactly. Somehow, your proteins in your body, in solution,
fold into the same structure over and over and over and over again. But nobody really knows why. If you can understand the mechanisms that
control the way proteins fold, you would have a very good way of trying to
prevent different forms of disease. My name is Alan, I’m an instrument scientist. I do neutron scattering experiments on a whole
variety of liquids and disordered material. Cancer, Alzheimer’s, dementia, any of these
diseases are almost invariably something to do with proteins not folding the way they’re
suppose to. So there’s been a huge debate going on about
what interactions with the water cause these proteins to fold the way they do. The current theory as to what water is doing
in this process is that water is basically passive, that’s it’s just a medium where proteins fold
up. Traditionally the idea has been that the water
forms like a shell, around groups in the protein molecular that
are called hydrophobic: they are ‘water fearing’. They dont’ like
water being around them. Water doesn’t like to form bonds with them. The idea was that it was these hydrophobic
groups that were pushing the protein into the structure it had. Most of this theory is based on computation,
which is a good thing, but it needs to be experimentally verified. So some of the work that we’ve been doing
is showing that water’s playing a more active role than previously had been thuoght. We think that it’s actually doing things like
providing a helping hand and allowing proteins to start that folding process. We’re using a technique that’s more commonly
used in physics to look at the structure of water around biological molecules in solution. To do this, we go to the ISIS Neutron and
Muon Spallation Source in order to do our experiments. Well, ISIS is a neutron source, obviously. Accelerates particles of protons, hit heavy
metal targets, which produce a neutron pulse by a process called spallation. We have a linear accelerator, and then a synchotron,
which groups the protons together into packets, then we run them down and hit them into a
target, and once they hit the target they spallate, and the neutrons then come off really
fast so we have to cool them down, it’s a process called moderation. Then after moderation we guide them in a collimator
down to be incident on our sample. We’re firing neutrons at our sample, which
is in solution, so it’s in the liquid state, and they bounce off your nuclei and interact
with each other when they bounce off and create a pattern which we can use to understand the
three-dimensional structure of what’s happening in our solution. If you think about a molecule that’s moving,
you’re going to take individual snapshots here, here, here, here and here… So in a way we can trap different bits of
our protein in teh process of folding. But at each stage we can see what the water’s
doing because we’re building up a comlpex snapshot of everythings that’s happening. Then you can put it all together in a picture
of how water is hydrating the molecules, how different the sizes of the chains are, how
far apart they are. Importantly we’re measuring on the atomistic
scale, so you see the atoms and how close the water atoms get to each other. I think the overarching theme that keeps emerging
to us is that water really is being active. It’s not just being passively excluded from
a protein interior adn then going about its business, it’s actually doing something. It has to be
there, and it has to be there to drive this process. So the water is acting as an intermediary
between the hydrogen bond sites on different parts of the protein and pulling them together. That seems to be the picture we’re getting
out of this. We don’t see evidence for this so-called hydrophobic
interaction. If we’re right about water-mediated processes
and water has a quite integral role to biology, then this has significant implications. It has implications for disease control, it
has implications for designing better drugs, that hydrate in the right way so that they
can map for instance the way hydration is in the place in a protein where the drug has
to bind to in order to have its function. But we may not be right either. This is the way theories develop in science. You take a set of evidence, and then you come
up with your best theory of that evidence and it works great until you get another piece
of evidence, and then it all falls apart, and so you have
to restructure your theory or modify it or just be proven wrong. I think as a scientist you’re not really doing
your job if you’re not proven wrong at least once or twice in your career. We’re working at the edge of stuff and just
starting to get new data so it’s not something that’s old. We’re pushing the boundaries of our techniques
and the way we think about things, and that’s the fun part.