You know

here you

go and.

Thank you David for the kind introduction.

It is this is my first visit
visit to Georgia Tech.

So it's been a great pleasure to come and

talk with WANT TO FEEL
faculty that you have here.

So thanks to all the folks who spent
time discussing with me today and

putting up with my dumb questions and
so on.

OK so
this talk is has has two parts to it.

And as we go through.

I expect you to be amazed and
order the why I managed to come

up with a title which the magically
link these two projects.

I'm just kidding.

So so well you could say that molecules
and membranes is the common same.

Of course in reality the aspects of
the that we model are quite different but

computationally mathematically and
in terms of physical mechanisms.

However I guess the same which in reality
links them is that you know I've been.

It to be a university and
it Institute down in Australia which.

Brought people from diverse backgrounds
together side by side within.

A bio engineering and
then a Technology Institute and

that just introduced me as a as a model or

two lots of different interesting problems
and you start to work on them and

then you start to see similarities of
issues you're facing in different areas.

OK So let me proceed.

I'm relatively new just three months
old now at a crucial of oratory.

But I thought it was incumbent on me.

Nevertheless to give a little bit of.

Kind of overall perspective if you will.

About the lab for those of you who
are who are not familiar with it.

So our analysis is always largest
science and Energy Laboratory it has.

A good sized budget lots of employees
the particular you know there are certain

things for which it's very well known one
which is of direct interest to me is.

The scientific computing facility there
which is a staggering in its size and

its capabilities.

It has a very large material science
program that's renowned in many different

areas and it has the pulsed neutron spill

ation neutron source there which
is I think currently probably

approaching two billion dollar investment
on the part of the government to.

Leapfrog the U.S. into a leadership
position and in neutron sciences.

So I've got a picture going forward from
there it's also home I should say to

the C.M.S. so what you see here
is this whole thing is sitting up

on top of a ridge the mine Pat of the
laboratory is actually down the valley and

they've built this place a neutron
source on top of the ridge.

This is where all the off.

Here.

This is the actual hole where the.

Boehm line which runs for like a couple
hundred meters comes into the hole and

then split up into all the different
installations with different

dedicated instruments for different types
of neutron experiments and this thing

here is C.N.N.'s it's and then a science
center right sitting right next to the.

To the neutron science and that's been
done across the country there's about five

of these newer science centers funded by
the DIA way around the country are there

are exactly five one of that
I Krige Brookhaven gone Berkeley and

Los Alamos Scindia and

in many cases they've been put
deliberately next to large facilities

with the objective Yes OK So.

They've been put next to last to
the large light facilities and

in this case neutron facility.

You know with the ideal that that we will
have cross-fertilization of our science

and that has been seen to be the case so
far and

we were will be will be extending and
ramping up those

the cross projects between ourselves and
our bodies next door going forwards.

These are just some
structural diagrams for

those of you who care
about the sort of thing.

This is your basic office of basic energy
sciences right up at the D O E and

they have three broad divisions or and
I think they call them divisions right.

This is the material science division and
this runs all the individual investigative

projects and
materials science across the country.

You've got your chemical sciences and
Bio Sciences division here which

runs all the individual investigative
projects around the country in that space.

And this one in the middle here is
the so-called scientific use of facilities

division and

actually monetary this one carries by
far the largest budget because it.

Running all these enormous equipment
facilities all the synchrotrons the light

sources the neutrons source at
Oakridge And here you'll see

these five men a science research
center is part of this whole portfolio.

So we're in that part of
basic energy sciences but

one of the things that I've
mentioned to a few people today.

Is that you know I've
come to I've become aware

you know sense of arrived in South to
settle in and learn about the place

that the fact that you have a science
center here which runs on one.

Sorry A and then a sun center
here which runs on one last.

Grant.

On the order of twenty odd million a year
as opposed to a whole bunch of small ones

means that we actually have
letter two to move and

do a range of different things
within the scope of our program

much more latitude than the folks
individual pay eyes on here or

over here can do because they have smaller
grounds more specifically defined and

so I was in the lab itself Oakridge lab.

OK So we sit inside physical sciences
Directorate you know the big Directorate

computing energy and
environmental global security

physical sciences and neutron sciences the
rest of it is kind of operational stuff.

So we're inside physical sciences and then
in there you'll find that you've got your

chemistry materials science
your physics and us.

OK And
what I'm getting around to saying is that

because we have more latitude
to move with this single grant.

I think that you know and

that is science goes on all over
the lab not just inside our center.

But we have latitude to be able to do a
range of different things which allows us

to facilitate cross linkages between
all of the individual grants

which would impinging on
than a science and so

we can be I think a really
powerful facilitator for growing.

All kinds of different science across
the entire laboratory in the bio.

Space in the material space in the energy
space in all these different things.

So I you know.

I think it's a useful kind
of foreign as a nation.

We have a half and half mandate half of
it is to support users around the country

who have their own projects they want to
come in and do with our equipment and

also engage with our people and
again if I can impart a sort of a flavor.

To these deal we funded nano science
centers because there are other ones that

are funded by any sand.

And I think is one out in California
which is funded by state funds.

We offer substandard collaboration's
together with the project.

So it's not just a matter of that.

Well we've got the equipment
you come in and use it and

then go back home and sort yourself out.

It's a genuine and collaborative
engagement and so you get more time and

more loving care when you come to
a deal you know in a science center.

OK.

I think I've done my path for
the lamp now.

So let me get on this was
a quick overview of different

things that group capabilities
within the center.

But you would expect this kind of
thing I guess in in a respectable

no science center surface
probing is a big operation and

a very very effective one hybrid
nanostructures organic inorganic and

pushing out into into Device
fabrication here to tell us this is

the main component of the chemical
functionality team we have a very strong

synthetic effort in Mecca molecular
in the molecular group very strong

theory team and
we have an on a federal facility there.

So but that should not just
be too surprising for you.

So look what I do now is I
come on to the bit about.

Well OK I've come
recently to two Krige and

I'm a Syrian computation person who grew
out of chemistry into no science and

by technology and so this is.

Just that it's a quick snapshot of a bunch
of different areas that we've been active

in with our modeling over the years.

And today I'm talking primarily about
I chose a couple of applications.

This one here relating to
a particular application of membranes

a rather exotic application I'll grant
you but I thought kind of interesting.

And then whirls We'll also talk some more
towards the end of the seminar about some.

Atomistic modeling we've been
doing to look at Victor R.

and I interactions for
gene therapy in the long term for

gene therapy understanding mechanistic
ways to help with gene therapy.

So we're looking at this sort of thing and

this sort of thing to die on the side of
that is a said we got introduced to all

sorts of interesting problems
by my experimental colleagues.

A lot of hundred stores where we've
done as with almost everybody else.

Done a lot of work on FOTA Tellus
with metal oxides systems on

novel electronic properties of mainly
carbon based textures of various flavors.

And then I ribbons and so forth.

We've done quite a bit of work on on
understanding the mechanism and foot if

the physical functionality in fluorescent
proteins and then this is my long time

passion which is reaction dynamics is
where I came from a long time ago when we

were doing gas phase chemical reactions
theory quantum scattering and so forth.

OK So let me then move on to
the first half of this talk which

is about the quantum sitting application
where we're at work where we're looking

at membranes so here we go look there
is there your favorite professor.

You know my understanding of the history
of this although I you know.

Truth be told it's you know looking at as
a topic separation by surface absorption.

Has kind of been done for a long time and

I was made aware of this by an elderly
scientist at U.T. Knoxville.

When I went gave a talk and he said Wow I
like this paper nine hundred sixty X..

And you know it's about if you serve
as a dog hydrogen or the Terry M.

and it as always was certain potential
well on a two dimensional surface

then because they have different mass you
expect different zero point energy right.

And so even on two dimensional surface
you would expect to have some degree of

differentiation between the two but
you know David and Johnson

this kind of kicked off a new thrust
in this area when they were looking at

you know one dimensional and sort of zero
dimensional they can find systems and.

Their calculations were predicting that
you could get tremendous selectively of.

Hydrogen from the Terry I'm in these
kind of systems if you get the right

exactly the right degree
of confinement and so forth

is favored inside these these highly
confined systems over hydrogen.

And this is it's really simple.

I've touched on already and
seen heads nodding as to why it happens.

You know go to the simplest system you
can imagine like a particle in a box and

look at your formula for
the quantum energy levels right.

And you know you see that
the dimensions of the box

come in here in the bottom line.

So if you make the box really
really small and confine it.

Then you'll be amplifying
the separation of the quantum

energy levels and you'll do that.

And likewise the mass.

If the mass of small I.E.
hydrogen or the tarry him again.

You amplify the difference between the
energy levels and so you know it comes at

the end of the day down to being able to
use the fact that deterrence heavier.

So it has a lower zero point
energy in a more tightly and

somewhat denser manifold of quantum
states compared with hydrogen.

Robot.

Translational quantum states.

OK.

And that's it right away just trying
to exploit this confinement effect

in order to separate them.

The other thing I should say about
the why is take a look at the partition

function here.

This is if you're looking
at an equilibrium kind of

had been skin you get it in their attic or
Librium and

of course you see temperature comes in on
the bottom line of the exponent right.

And so you.

So if you want to amplify
the effect of this difference

in energy levels you need
to go to low temperatures.

So this is a low temperature
separation problem.

It's quite important to
understand that going forwards.

And what that means is that if you have
any kind of significant barrier involved

that will kill your kinetics.

And you won't get much
flux going through so.

So we've got to be careful
about various here is not a lot

like we can run this thing at three
hundred Celsius or anything like that

we're looking at applications it'll
take us down below one hundred Kelvin.

OK.

So the so-called Librium
sitting idea that David and

Carl introduced is a wonderful idea.

But of course there
are the fabrication issues.

And that you know it's
not that easy to make

these nanotubes with exactly the diameter
you want and lots of them and

all stacked in and
a nice why and so forth.

And so it was my colleague
at in Brazil Brisbane him.

David and I was Suresh but.

Who came talking to us about another
idea he had that might allow

an easy A fabrication potentially of

a sitting with a quantum sitting material
and cigarettes His idea was that you could

make micro pores carbon
materials much more easily and.

If you have you know a system
like this with ink and

interconnected cavities right.

And you can get some degree
of control over the you know

the bottleneck so the poor the poor mouth
between the cavities by the way that you.

Well I don't know how I do it.

As a theorist but
the way that you that you.

Track it and make the material gives you
some degree of control over sizes here.

And.

You know the idea was that you know if
this was the right determining step to hop

from one cavity to the next one and
the confinement was about right there.

Then you should get to Terry I'm going
through more easily than hydrogen

because you know it's got to because
it's got lower energy states and

at low temperature it can access
those more easily hopping through so

usage should see faster diffusion of
the Terry and and this is then going from

equilibrium sieving in the case of a long
in a tube to what they call kinetic

savings that's controlled by the flux
through these confined transitions States.

OK.

So I in principle this
should be easy to make.

So not really going to turn out
that way but that's the story.

We need to run through.

So it's the rich came to us and
said Could you help us with the quantum

aspects of the calculation and
we said Well.

Sounds good.

And so we started to look into this and
you know we started with first principle

models that are very very simple but
truth be told the structural details

of these kinds of materials are in
themselves relatively poorly known.

So it was about as good as anything else
that you might want to start with and

so let me start just briefly with the with
the simple theoretical framework that we

start with which I understand you folks
familiar with because you have a kinetic

six bits here on your faculty which
is transition site Syria right so

here's your transition state expression
for the rite of passage through

a transition state some kind of
a bottleneck or a barrier right.

And you know it comes down to a partition
function at the transition state

divided by the partition function for

the reactance in this case the reactant is
the free hydrogen molecule to Terry M and

the transition state is this molecule
not confined within a narrow poor mouth.

OK.

And so this is a free rotating system
the vibrations are high frequency in

relatively small physical.

Relatively small distortion and

so we're actually going to treat
these molecules as frozen.

But the big difference in entropy comes
from the fact that it was rotating freely

out here and translating freely but inside
here it's not confined both rotationally.

And of course translational a by
the narrow poor mouth and that makes

this thing quite different behave in quite
a different way from that one there.

So this is kind of the simple models that
we set out we started with a little nano

two fragments to represent
the poor mounts right.

And if you put your hydrogen inside one
of these and think about how it moves.

Well it's got it's a two
it's a linear molecule so

it has two dimensional rotation which is
hinted inside this confined space and

then it has also two
dimensional translation.

Perpendicular to the zit axis and
there's that axis is their

reaction coordinate OK to get through and
so what we have here

is actually four dimensional coupled
motion in the transition state right.

And we have to calculate that thing which
means we need to get the we need to

calculate the quantum eigenstates of
this handed rotational translational

molecule and then some up appropriately
to get our partition function.

So we do that.

This is the second Test at
the end of the lecture.

Basically it's a four dimensional
Schroedinger equation.

Here's your X. and Y. coordinates for
the translational motion right.

And this is your two dimensional
rotational Hamiltonian for

the molecule doing this
rotating like this.

And then you've got your
potential in there.

I should say that we started this
out using letter Jones interactions

simply because it's so
very expensive to calculate for

us from Ramallah tronic point
by point electronically.

We're using Linux joins in here and

exploring the qualitative effects
that we're going to find out of this.

So not surprisingly you get selectively.

Which is you know it's kind of similar to
what you would have seen from equilibrium

sieving not surprisingly
because it's just confined in

a little negative fragment right.

And so what we're doing here is
plotting how the selectivity between

the selectivity ratio for
the Tyrian versus hydrogen

goes up at very low temperatures and
so this is what we're talking about

low temperature application is because
you need to amplify the difference

between deterioration hydrogen down
there at low temperatures right.

OK That's all fine and
you know we published it but

it's not earth shaking in its conclusions

because you kind of expected to be
consistent with what was seen before.

But here's a funny thing.

And here is why you know
initially my colleague Suresh

was talking about the light type materials
and in fairly quickly they switched over

to carbon materials and I think that
part of the thinking there was that.

This is low temperature and so you need
to ideally to get rid of any barriers.

Otherwise you'll have terrible kinetics to
get stuff through and you know with carbon

and hydrogen interacting you have this
attractive winner Jones interaction and so

if you look if you if you move your
hundred into wards the the poor mount

here and you plot.

You can let it move around and find at
any position what is its minimum energy

its minimum potential you get a plot
that looks something like this.

OK.

And it's down hill.

So there's no intrinsic barrier to getting
into this into this poor mouth and

what that actually tells you is
that when it's sitting in here.

It's actually feeling Littlejohn's you
know there's a there's a if you plot

the legends potential
there's a little well right.

And it's just at the sort of sweet spot
where it's feeling this attractive while

all around this little negative fragment
which makes the poor mouth surrounding it.

So it kind of likes it there
right now if you touch it.

This is we've got some plots here for
different science nanotubes.

The story is you've got
to get confinement on.

Around about six or
seven angstroms diameter

to get a combination of
a good separation but

also no major barrier that would kill
the flux going through all right.

If you make it too tight.

Yes you get wonderful selectivity but
it'll never go through at low temperatures

because there's a barrier
to squeeze through.

OK so it's a kind of a it's
a tradeoff of these effects.

OK so.

It might have triggered in your
heads already possibly maybe not.

It's OK I'll point out here.

There's a problem with
what I just showed you.

Because when I started this out.

I said this is going to be a transition
state this is where we're going to get all

selectivity happening going through here.

Right.

And so hopping through you get more and

more selective as you go
on through the membrane.

Yeah but
that's not what we're seeing at all.

We're seeing the potential
as a minimum here and

it gets higher here in the cavity.

What's said all about.

If that's the case your hundred and

wants to stick here doesn't
want to come out there right.

And if the potential is higher out here
then this becomes your transition and

then your selectivity is going out
the window because you don't have

the confinement here right.

So there's a theoretical problem.

Maybe with maybe we never should've
started with the first principle model but

that's the way we are as chemists right.

So and So
what we did was we then went ahead and

we thought well what is the potential
look like for a typical.

Instead of just looking at one little poor
mouth let's look at a what we're seeing

might what possibly represent a poor mouth
and a cavity and see how it looks so

here's a little mimic model for a
constrained poor mouth and a larger cavity

which is a large and then a tube fragment
surrounding these little guys in here.

All right.

And we can track the potential
running from outside through here and

find where does the hydrogen go to
find its minimum energy path right.

And this is what the minimum energy
pathway looks like as you go through.

It's not bent man it's
a potential curve right.

So so here we are right in the poor and

the poor mouth where
actually it's minimum right.

And then it gets a little uncomfortable
when it's pushing out around the edge here

that's the spike and
then what happens is it moves out here and

affectively its surface at Zorba onto
the inside of the larger cavity wall.

Because here on the on
a sort of a larger surface.

It's only feeling the attractive
Lehner Jones from half of the space.

Where is inside here.

It's feeling the attractive
linen Jones all around right.

That's why the potentials higher in
the cavity compared with the with

a poor mouth.

And I don't care about these spikes
they're just out a factual because the way

we constructed are particular model we
could construct a different model and

this these features would change but

what I do care about is
the relative energy here and here.

OK So there's a there's a problem.

And these are just the these are the plots
of the actual structures that correspond

to those geometries this is on the edge
coming out and there's effectively

something which is surface absorbed into
the larger cavity wall inside there.

OK.

All right so and
this is really illustrating what I'd wipe

my hands about before about the fact that
it feels the sweet spot in the poor mouth

of these this little
JONES Well all around.

Yeah.

Whereas when it's in the bigger cavity
it's only kind of getting that from one to

one half of the space which is nearby.

So it's energy is kind of high around.

All right so we've done this and
I want to say anything more about that.

What were the implications of that.

Well.

You know the implications are that
the ideal selectively The There would

be predicted for now are poor man's may
not be achieved because it isn't clear.

That passes through the poor mouth is in
fact right determining it's not clear.

That's actually the better the transition
stage at all in these systems

we did look at different models and
we found that for

some special shapes like
a fullerene likes fear.

You can get the energy lower in
the cavity compared with the transit with

the poor mouth.

Yes surface very special
combinations of geometries

you can invert those energies and get
what we thought we had at the stat right.

But that implies you have serious design
issues to optimize this kind of effect

because then you've got to control.

Not only poor some poor mouth size but

also shape of the cavities in between and
that's non-trivial.

OK so where to from now on this is

an interesting paper that Suresh published
with some colleagues in France who

helped him do the neutron
scattering the effect is real.

So the fact that to tear into fuses faster

at low temperatures has been
verified by this kind of experiment.

So it's real but the question is
can you actually optimize it and

turn it into a functional technology.

And that's open question but

I'm really just going to finish this part
of the talk with an interesting flight

of fancy which is a suggestion of maybe
one route towards being able to do this.

So the idea here is if we have design
challenges with you know a means of porous

kind of system where you have to control
cavities and poor mouth and so forth.

Let's just do away with the cavities and
try and start with a thin membrane

where the only thing we have to
control is the poor mouth size.

Right.

Would that work.

Maybe.

And there are some so-called systems
which are now being synthesize so

this is poorest graphene type system which
has natural holes in it which is saturated

with hydrogen it's done by
a pull America politicization

prices on a particular kind of
surface where they can make.

This kind of stuff with holes in it like
a graphing sheet but it's got holes.

And you can make this kind of thing which
is called Griffith Carbonite tried.

It's a combination of carbon nitrogen.

And it's got triangular Kev It
is got triangular holes in it.

OK we try to few of these different
ones which have been synthesized

basically the holes are too small from
the ones that have been made already.

So yeah there's a barrier to
getting the hydrogen through and

that's going to kill your kinetics for
a low temperature application so

transition state theory
sort of said this already.

So I'm going to blow through it.

Poor thing.

And that's the science by the way.

Three point angstroms a little too
small to get a good kinetics at the low

temperatures.

And you can see it here.

So actually the sense is inverted
here this out here now is large

separation in coming this way we're
moving this thing into the poor mouth but

you find now we've got a point for

even a barrier this is density functional
theory corrected for dispersion effects.

So you have a significant barrier
which means the hole is too small.

Right.

All right.

Selectively what you can
calculate your selectivity is and

again I don't want to dwell too much
on it simply to say that you know

if you calculate the selectivity for
poorest graph and it looks wonderful.

But here is you're right
it drop it drop through

the floor as the temperature goes
down because of that barrier and so

we really want the right to be going
the other Y. at low temperatures.

If we can get rid of the barrier.

Right.
So you could try that and this one has not

been synthesised we picked it up from a
calculation that was done by actually one

of my colleagues now at Oak Ridge where
they envisage functionalize in porous

grafting with nitrogen you know which
basically takes away the hydrogens here.

And so now you get a larger whole.

Five point seven angstroms That's not bad.

It's a round about right.

From what we already knew looking
at the nanotube systems right.

And so you can go ahead and
calculate that one.

This is an energy profile for the system.

It's about a point one even sliding on in
there and you can do you calculations.

These are the minimum if you structures.

You can do your calculations here here's
just selectively this is your right for

going into the poor into
the poor mouth it's all right.

There's a catch in this that you've
already seen in the previous

part of the talk.

But I want to show that at least
in principle it looks all right.

But let me point out the obvious problem.

Yeah.

Here is your poor mouth.

But again you've got this problem you have
a sweet spot here for the interactions.

What happens when you come out
the back side of the membrane.

Potential is climbing up again and it's
symmetric so anything you gained on the Y.

in with selectivity you're going
to lose on the way out right.

So no good having a membrane on
itself on its own which isn't

which is purely symmetric it doesn't
help at all right we need to make this

asymmetric by pulling the potential
down on the back side.

So we have a one Y. pathway through.

And this is the little postulate that
we have it grew out of what worked and

we've been doing one hundred storage where
we knew that if you decorated graphing

like systems with metals hydrogen
likes to stick on to the metals.

So that's where the idea came from.

Let's stick or write a membrane on
the back side only with a metal.

So then when the hydrogen comes through.

It'll see the metal and
it will want to go stick to the metal

on the back side and so you can drop the
potential down and this is a couple of.

Energy profiles one is where you decorate
the backside with lithium and this is

where you decorate it was titanium right
and that's the symmetric One was nothing.

So there you go you can in
principle decorate one side make a.

And I symmetric membrane you know
one white pathway through and

get the selectivity and

the right constants working in your
favor as you go to the low temperatures.

So I've been talking with colleagues about
how easy it is to make stuff like this and

the answer is well experimentally they're
not there yet they can make certain kinds

of systems with holes in them but they
can't get make them with the right size.

And they're still working on ways to try
to kind of get control over the precise

size of the hole in this two dimensional
mannish there's a few ideas that we've

been kicking around that we'll have
a go at but we're not there yet.

Experimentally So
this is just some interesting ideas that

we hope will stimulate and
inspire our experimental colleagues.

So they were Yeah that's all I wanted to
say about that particular quantum isotope

separation project.

I'm going to switch now to discussions
about a whole different sort of thing

which is in the biological space and
this is a shorter part of the talk.

Actually not because the calculations were
short of these calculations take a long

long time to run.

So it was kind of a labor of
love to get them done but

this space is kind of so new that
really I can summarize it in a short

space of time because at
this stage we're running.

Heavy duty simulations and we're really on

extracting extracting qualitative
mechanistic information back out of it.

So it's easy to kind of run through and
summarize for you.

So what's the deal here.

All right we've got.

OK.

You have got a mass here so
use that the deal is that

we want to for their for
all kinds of reasons.

It's one wants to be able to introduce
genes into cells and you know if you're

looking to make drugs which
are proteins then you want to use the.

Well as a little factory.

So you want to feed as much of
the requisite D.N.A. sequence as you

can into the cell and get it to cook and
make this stuff and then harvest it right.

If you're doing plant biotechnology then
obviously you're looking to get as much as

you can of a particular
protein a particular D.N.A.

sequence into the cell in order to.

An irreversible way modify the way the
plant is expressing and then the other one

here which is this particular application
focuses on is what's called gene therapy

and this is where you put in
Short Strand R.N.A. into the cell.

And what it does is knocks out
the production of certain proteins.

And so there are certain diseases
neurological diseases which are cause it's

known to be caused by over expression of
a particular kind of protein which clumps

together and makes and causes all
these dreadful medical issues and so

ideally we'd like to be able to knock out
production of those handful proteins and

one way to do it is to get a particular
kind of R.N.A. Short Strand R.N.A.

into the cell and
it basically messes up the transcript

the transcription process for
the harmful protein interferes with it.

So it's interference and
why did we get on to that.

Well the reason we got onto it is
because it Short Strand R.N.A.

twenty odd base peers.

Which means that there's not too
many atoms to deal with all right.

I remember once being in a meeting
with my colleagues in the institute in

Australia and you know they get data for
different kinds of.

Gene delivery experiments and data is all
over the shop and they have no clue why

something works and something else doesn't
in terms of getting it into the cell and

you know basically what they
have to do is that the R.N.A.

is negatively charged on its surface.

And then.
Need to coat that with something

else it'll make it look positive from the
exterior so that it will nestle up next to

the cell membrane which is and has a
negative charge and then it'll stay there

for a while and get envelops into
the cell through into psychosis right.

And I also have to have stuff clustering
around the air and I had to stop it.

Getting attacked by end zones which is a
defense mechanism outside the saw membrane

before you can get in.

So it's probably disguised thing and
it's partly a electrostatic thing to help

it get up next to the membrane and
gets into the cell envelop into the cell.

And so you know they get data
which is all over the place and

one of the first things I'll ask is
Well what do we know about the complex.

That's happening between the I or
the plasma D.N.A.

and the thing which is supposed to
be clustering or enveloping it to

protect it and get it into the cell
which is called Vector typically.

And the answer is they know almost
nothing about that complex process and

and you know made a little serial killers
puts up minuses where you know we

could simulate stuff like this and
I said great.

Can you do it.

Thousand by Spears.

No sorry too big.

Right.

But the nice thing about gene therapy with
our an eye is that it's Short Strand and

you can actually you can do that
in all the Tomic detail and

look at the complex and
that's what we got onto it.

So this slide was to show the sort of
general concept mechanistic concept and

this one by the way shows that the R.N.A.

being stuck between
layers of a nanoparticle.

Which we come to right at the end if
I get time and I may not have time.

So this is one way that you
might think about protecting

the area is envelop inside
a clay nanoparticle which

has positive challenge in its layers it
will bring the negatively charged inside.

There's another way they're going
to talk a little bit more about in

a second which uses small dangerous
to cluster around the air and I But

you know that Santa so Tarsus.

Picture in a very simple minded way.

OK so this Victor is the thing and

everybody has their own favorite carry a
particle to get the R.N.A. inside the cell

and so you can use catatonic Lippa
zones you can use polymers or

dangerous you can use inorganic carriers
and what I'm going to talk about right now

is a small dent which is what one of our
colleagues and family has been working on.

So these are small peptide in dramas.

Which have a main functionalities on
them which become positively charged

under ambient conditions.

So they're pretty small compared
with the size of the are in a.

And you know he has particularly
exquisite control over.

So this is of these things so that he can
do all these tricks of isometric synthesis

to put a targeting leg end on one side and

have the I mean functionally on the other
side and all this sort of thing.

And so we got started in just trying
to look at the basic complex ation

events that occur to get some
qualitative feeling as a start

of the white down the road to getting
a better understanding of mechanism.

So we have Short Strand here.

With about twenty odd based peers as you
can see this is the particular one that's

used clinically in studies at the hospital
in Brisbane for cervical cancer.

So they're all cancer around.

The word failing me but for
prevention of cervical cancer.

OK And then we have these little
dangerous which are in this case smaller

than the R.N.A. and we start out simple we
look at one of these guys clustering and

I think I got a this is
just a series snap shots.

The total time from here is
about thirty nano seconds.

There's water all the way through this but
we don't show it.

So it's a fully solve dated kind
of system we're looking at.

And you have counter ons
to balance your chair.

And so you can see it kind
of if it's small enough.

It gets in there and
it nestles into the major groove right.

So this is one we started out
outside a mine a groove but

ultimately it finds its
way into the major groove.

You can start on the other side in a major
groove it'll go into the major groove and

you can see this progression right.

And so
it ends up stuck in a major group but

in a different location around the helix.

And so you get different winding
energies depending on where

in the major groove the tide
actually ends up locating itself

in principle you'd like to do a whole
bunch of sampling if you want to

calculate real authentic chemistry's of
this process or that's just too expensive.

We can't do it.

At this stage and so

we're dealing with qualitative information
that comes out of these simulations.

You can take larger ones
these are the other ones were

four plus a little bit bigger and

these ones now don't fit nicely inside
a major groove and I start to wrap around.

OK.

And then going forward from there.

You can start to look at something a
little bit closer to what experimentalists

do is that they try to dial up a lot
of positively charged vectors which so

that the so that the ratio of positive to
negative charges perhaps two to one or

even up to four to one the idea being
they really want to have the hour and

a cased and protected and
and so forth and so

we can start out with a whole bunch of
these dangerous and look at the way that

they were complex on to that R.N.A.
this one actually shows the water.

All right.

And we can see you know
where is essential.

Right.
What's the frequency of popping on and

off and so forth for these systems and
these are against him.

Snapshots on the way through
the simulation that show you the thing

as the as these dangerous
cluster all around it and

you know the coming on and
off all the time in a dynamic equilibrium.

The other thing I should say
about the why is that we can

infer some mechanistic qualitative
mechanistic issue such.

As I've been describing here for

the complex nation that's
occurring outside the cell.

But of course once this thing gets inside
the cell it goes in through the end design

in design brags dampen it gets
out into the side of Plasm.

And then of course the R.N.
Ai has to release the dangerous again

because the air and I has to go and do
its interference thing in another part of

the of the US cellular machinery and
so it isn't just complex.

It's also release which is important.

Kinetic So
both of those prices are important.

So one of the problems for

example was lodged in Druidic carrier
particles that they found is that you can

use a big denture my Which will envelop
this entire R.N.A. inside it right.

And it protects it nicely.

They can.
Shari through fluorescents McCraw Skippy

that it goes wonderfully into the cell but
I don't get any knockdown and

transfer action of the of the of
the protein that we're trying to stop.

And the reason is because it won't
release again and I stuck and so on.

It's not getting out.

Right.

And you can show that if you label the den
drama and the hour and I separately you

can see from single molecule fluorescence
that they're not separating right.

And so the complex action but

also it's reverse is an important part
of understanding the whole process.

And look that's more or less where we
are we've done the other simulations but

it's at the same level of qualitative
observations at this point in time.

One of the things that interests me about

being in our grid now is that of course we
have the neutral guys right next door and

we can use neutrons to study this
kind of process as well which is

a whole different ball game from
the fluorescence my cross campaign.

So some interesting possibilities but

we're really just starting to put
things together at our coverage.

The last thing I was going
to show was we also did

a lot of work along labor
of love on building.

These kind of inorganic not a particles
with these layered structures

where you know these layers have positive
charge it's a magnesium hydroxide system

that has been doped with Ela many I'm so

magnesium to appliance element in three
plus once you substitute element even for

magnesium lattice side you've got
a one plus net positive right.

So when you don't pin thirty percent of
alimony I'm into these magnesium letters

science.

You've introduced positive permanent
permanent net positive charge

into these layers and what it then.

Does is it draws encounter
ions to balance Chad.

And so you get little chlorides or
nitrates or

whatever in the gallery
space into balance.

OK So of course our an eye is negatively
charged too it's just a whole lot bigger.

So it's also possible to actually
get these things to open up and

get our and I in there as the counter.

And effectively to balance challenge.

And so this has been explored in our
colleagues in Australia were using these

kind of nanoparticles to
deliver into neural cells and

had some quite promising results
not not yet the Holy Grail but

promising and so we spent a long
time to set up simulations of R.N.A.

inside these kind of
layered systems as well and

you know the same kind of
qualitative observations but

I don't want to go into that because
you can see the pictures and

you know it's more of us tell you sort
of where we're at with this we've set up

the hard way to do it but
we still have time to go and

importantly we need to get the dialogue
going with the experimentalists

to find what's the best way to interpret
these kinds of atomistic results.

There was something else
in my head just in.

But it's gone.

So I'm not going to going to lie anymore.

OK that's it folks.

I want to thank my colleagues
who helped with these projects.

These are so at the top.

So you see the students and
postdocs who were involved in this work.

I last about an hour and a half of work
in the hotel this morning which is rather

annoying for myself and predict who
is going to have breakfast with me.

But what I patched together and

haven't got the names in yet is that
the young lady up there is the gentleman.

MALISE.

Hankel is the.

One in the middle.

They worked on the all contributed
to the membrane calculations and

these are my academic collaborators sir.

Ben and Steve Groene up at Argonne
National Labs in my sister center and

then a material center up at are gone but
Steve like myself

has come out of chemical dynamics
background so we both have that kind of

quantum dynamics bent to our
attitude I suppose you should say.

And then these are the folks who've been
helping and working together with us on

the vector R. and
I stuff defined as the Ph D.

student who developed the peptide
based peptide simulations.

John worked on the not a particle
stuff and also did at the top there.

These are the academic collaborators
down below Harry Perec is

the guy who does the Denver most synthesis
in the pharmacy school that you Q..

And Dick to hurt in that Heidelberg and
to be a quantity to it.

Who's doing the single molecule
single by molecule fluorescence

studies on these complexes.

OK thanks everybody.

There may well be and
you know I think this is.

You know Suresh the chemical engineer or
model or wanted to go ahead and

do molecular dynamics studies of multiple
oddities going into cavities and

look at those sorts of CO
potentially co-operative effects.

And I'm not sure how far
he's gone down that pathway.

You know I asked feeling was that.

If hydrogen wants to stick
in the poor mouth then

you've got a bit of a problem
with your kinetics at the outset.

And so while you might be able to try and

pack pack him into the cavity you still
got a kinetic issue confronting you and

because our calculations are intrinsically
rather more expensive and

then the cons of calculations
that Suresh would do

you know we sort of thought well
when we don't we're not we don't

really want to go down that path yet if
we find there's another strategy that has

a better chance of success but
I wouldn't say that it's not worth doing.

It's we've just tried to identify what
might be a better strategic way to go move

pushed our efforts in that direction but
I wouldn't say that that story is closed

with music pours materials like.

Yes yes yes.

OK so if to Terry I'm goes
in faster than hydrogen and

the potential symmetric than one hundred
it will come out faster than did.

Sorry let me get this right material
guys in with a potential sliding one

way that means that when you come out the
other why you have the opposite effect.

And so basically it kills you.

That's what it comes down to So.

So if I could explain that.

In that poor mouth to tearing
has a lower zero point energy

some more attractive potential and so if
you're thinking about us low temperatures

thermal system the deteriorates it's
more comfortably and goes in court.

You're right.
The trouble is that hydrogen is now

sitting at a higher energy
relative to the exit so intense or

getting out again it's easy if one hundred
because it's not so deep down in the well

so hydrogen comes in slower but it goes
out faster compared with to tarry and

the effects can't basically cancels itself
out unless you can find a way to make it.

I symmetric.

OK.

Yeah.

OK.

Yes OK The reason is because once you get

inside the cell the PH drops and those
lead double hydroxide will dissolve away.

Whereas Adric systems Donda and
so that's why

the nano particles even though they allow
that can actually affect the delivery.

There is still an open question
about toxicity because

you're in a Hansing the concentration
inside the cell when that happens.

OK that done quite a lot
of studies of intake into.

Neurons.

Collaborating with the brain instituted
uku and well you know they'll show you

this lies which show selves that have

taken these things in and they sort of
look OK to me who doesn't know anything.

But other colleagues who are working all
the time with these kind of cells will

look at it askance and sigh Well it
doesn't look all that healthy to me.

Yeah it's not clear yet
whether the toxicity thing is really OK or

whether it's not but what you certainly
know is that they do deliver because they

dissolve and it's not catastrophic for
the cells but

you need to do a lot more studies before
you could really be sure with Saif.

Yes or

no structures.

Yeah you can make them with a mixture.

That's correct.

And so one of the things is that for
example the exterior ones.

If I get this right.

Are second Raymond's and the interior
ones a tertiary if I got this right.

So the external ones present first and

then then once it goes inside
the design the PH drops and

the internal ones will then part night as
well so they can get the can differentiate

right and that actually is a has a rather
interesting swelling effect which you can

tie in with models that they have for
in design breakdown.

Which is another paper but
I won't go into it.

But yes you can you can go.

If you can do it.

How much does they.

So well the why function is just
as critical as the energy level

because they parrot right.

So when you when you.

When you diagonalize your four dimensional
Hamiltonian you get eigenstates out of

that and those like in states have
the allowed to quantum energies right and

coupled with each of those is a Y.
function.

So the information is all in there.

For the purposes of this particular
description I focused on the energy levels

because you can say well look that's
got lower energy that's got higher

energies are lower temperatures the lower
energy one will dominate right.

But the wife functions are intimately
involved in that whole process

because they're part of the solution.

And the other thing I should say is
that the transition state Syria itself

is a model theory if you
want to do it right you

should do a full quantum scattering event
through that poor mouse which is much more

intensive computationally the reason
we think we can get away for these kind

of rough purposes with transition state
series because there's almost no barrier.

So we don't expect huge
amounts of tunneling and so

forth which would be really important.

If you had hydrogen which was
sneaking through a barrier.

So that's one of the one of the reasons
we thought we could actually use

transition sites there at the outset.

Even though it's hydrogen at motion.

Thang.