Developer Chat

betahelix Hi
everyone, thank you for coming to our Scientist Chat!
katfish Hi
everybody! We're going to start our scientist chat soon
porkythepundit Hi
everyone
drumpeter18yrs9yrsIRC i finally
made it to a scientist chat
betahelix We're just
waiting for our BakerLab scientists to connect (mibbit is
slow on their computers for some reason)
TimovdL chatzilla
is easier
auntdeen2 maybe time
to start doing the chats in Google Hangout w/ broadcast
betahelix bk and
Aaron are here from the Baker Lab
Aaron Hi
everybody
betahelix Aaron is
going to talk about the new Flu Puzzle we just posted...
take it away Aaron...
bk Helloooo
silverbergirc Evening
drumpeter18yrs9yrsIRC that would
be cool to do a vchat
Aaron Yes, we
are trying a new approach on this puzzle, trying to find
improved stabilization
silverbergirc *crosses
fingers the ED puzzle won't crash*
drumpeter18yrs9yrsIRC its an old
ED that have all the information they are going to get. .
betahelix But today
we're talking about the Flu!
drumpeter18yrs9yrsIRC oh
silverbergirc OK. Shhot.
silverbergirc Shoot.
Aaron Lemme
start with a little bit about the old puzzles
Aaron just to
get people warmed up
betahelix (and I'll
mention something about the next ED puzzle at the end of
today's chat
Aaron So in
previous flu design puzzles we were essentially trying to
use the foldit players to modify some of our exisiting
binders, that bind to H1 Influenza, to bind to H3.
Aaron Just so
people know, the two most common seasonal flu strains are H1
and H3
Aaron Our lab
has had H1 binders for a couple years but H3 is a harder
target for us
Aaron We
essenentially docked the old H1 binders to H3 and then had
you all try to find mutation that would work against the new
bound target
Aaron We had one
puzzle where we docked a helix in and one where we tried to
complete binder
drumpeter18yrs9yrsIRC i didnt
even know about the flu puzzle
Aaron However,
when we tried some of these different helix solutions in the
lab they didn't bind
Aaron we've
tried many helix based designs against H3 but none of them
so far have worked
Aaron We are
starting to think that though we can get a helix to dock and
bind to H1, they just don't work as solutions to H3
TimovdL Give us
more freedom
drumpeter18yrs9yrsIRC you can
ask nicely
Aaron AHA!
Aaron yes
Aaron We thought
we were very close to an H3 binder with the helix based
binders, but alas not
TimovdL very
restrictive and dull because of that
Aaron so we
originally didn't want to stray to far from what we knew
worked for H1
Aaron Ok, so
that is a bit of the story on trying to find H3 binders
Aaron let me
tell you about this puzzle
Aaron One of the
things we've found out in lab, through testing, is that
though the H1 binders bind very strongly
YoyoParis I want a
contest !!!!!!!!!!!!!!!!!!
BletchleyParkirc Please let
Aaron finish his story.
drumpeter18yrs9yrsIRC its 3:14
pm. its pie time "D
Aaron they are
not particularly thermally stable
Aaron There
melting temperatures are quite low
YoyoParis this is a
problem ,
Aaron And one of
the side effects of low melting temperature is that they
could get degraded quickly by proteases in the body
Aaron Floppy
proteins are easy targets for getting chopped up
drumpeter18yrs9yrsIRC what was
with the score exploration restriction on the beta puzzle?
YoyoParis because
Rav find the hydropuller
Aaron If we are
trying to design a therapeutic, but the proteins get chopped
up quickly in the blood, it will never work
betahelix @drumpt it
is also in this new puzzle
betahelix You can
read about the RMSD condition here:
Aaron so the
information we know is 1) The interface residues on the
current binders work quite well
CarlosBandito How will
ye solve dis problem?
BletchleyParkirc Please let
Aaron finish his story.
Aaron 2) The
scaffold, the protein the binder was originally designed
from, is from a snapdragon flower
YoyoParis no Myryam
as the best
Aaron 3) This
means it evolved in temperate climates, and would have never
needed to be particularly thermally stable
YoyoParis there is
no climate
Aaron 4) There
are similar three helix bundles, like the one in flu
puzzles, that came from thermophiles and are much more
thermally stable.
Aaron *similar
to the one in the flu puzzles
Aaron 5) The
thermophilic three helix bundles usually have a much better
packed core than the known H1 binders we have
Aaron SO, if we
can build a better packed core for the H1 binder, and have
the same interface residues, it could lead to a more stable
protein and a better therapeutic
Aaron that are
the design consideration for the puzzle that is posted now
Aaron feel free
to ask me any questions
drumpeter18yrs9yrsIRC this will
be very fun
marie_s it will
work for h1 only?
TimovdL So we are
to design the core and not the interface?
Aaron @marie_s:
this design binds H1, H2, and H5
Aaron (not H3)
Aaron I'll
elaborate
Aaron there are
three main groups of Influenza
bk @Timo,
design is disabled for interface sidechains in this puzzle
Aaron and
Influenza B, which is so different it is kind of it's own
group
Aaron This
puzzle is directed towards Group I binders
Aaron the most
prevalent of which is H1, and why I reference that the most
TimovdL How do you
know if high scoring cores are stable in the way you want
it?
drumpeter18yrs9yrsIRC im
guessing testing
Aaron Just so
you know, the question that TimovlDL we are discussing right
now
drumpeter18yrs9yrsIRC its a
little laggy
betahelix @drumpeter
you are right, but we obviously can't test everyone's
solution
Aaron it's kind
of a slippery question because we know Rosetta/FoldIt has
some pathologies that crop up and we want the most stable
real designs to score the highest
TimovdL that is
why I asked
Aaron Ultimately,
we won't know the answer until we actually make the proteins
and test them for stability
drumpeter18yrs9yrsIRC i figured
yall would test or yall could tell just by the aa in the
core.
frood66 if we are
principally working on the core and not the interface
wouldn't we be faster with just the helices in question in
the puzzle?
jamiexq Is there
any way to give us temperature info on our folding solutions
like they provide in etRNA?
bk @Timo, we
also want to make it easier for players to pick their own
solutions to share with scientists
silverbergirc Good point
frood
bk that's in
development right now, and hopefully will be available to
you guys soon
Aaron We will
definitely be looking more closely at the core residues and
are working on developing our own filters to score those
TimovdL Is there a
way to score thermo stability?
Aaron @frood66:
We wanted a little more diversity than just locking the
backbone and rebuilding the core.
frood66 ok
Aaron We decided
that allowing a small amount of backbone movement would be
suitable but only if we presented the puzzle in the bound
state, so the context of the interface is still there
marie_s the 2
little ends are linked to other parts?
Aaron @janiexq:
Short answer no. But well packed cores, with as little free
space as possible, correlate strongly with higher melting
temperature
jamiexq thanks
drumpeter18yrs9yrsIRC yea, the
locked one was hard.
Aaron @marie_s:
yes actually
Aaron they are
further aa after those ends, protein tags that lack
secondary structure, that we use for some of our experiments
marie_s it is
tempting to fold them inside
Aaron those ends
needs to be EXPOSED
brow42 the ends
have the highest deviation in my beta test of the
puzzle...perhaps those should have constraints.
Aaron we are
hoping the RMSD filter prevents the ends from being folded
inside the protein
disturbedxxx666 IMAGE: href="http://fold.it/portal/files/chatimg/irc_398223_1369341575.png"
rel="nofollow">http://fold.it/portal/files/chatimg/irc_398223_1369341575.png
drumpeter18yrs9yrsIRC i just
noticed this arrow
drumpeter18yrs9yrsIRC natural?
betahelix that arrow
is disturbing, disturbedxxx666!
brow42 that looks
like the last atom is flipped 180 degrees.
drumpeter18yrs9yrsIRC me and
drumpeter are the same person
drumpeter18yrs9yrsIRC me and
disturbed are the same person haha
porkythepundit me am
disturbed. lol
drumpeter18yrs9yrsIRC no.
betahelix disturbed/drumpeter,
is that in devprev?
drumpeter18yrs9yrsIRC yes
marie_s just the
shape of the flu is strange
betahelix we'll
mention that to the devs
drumpeter18yrs9yrsIRC that
shouldnt be there, should it>
drumpeter18yrs9yrsIRC ?
betahelix (about the
arrow)
Aaron Heh,
that's all I stare at ever
TimovdL Why
handfolding, optimizing a structure is not very good while
handfolding
Madde I found it
too, it's A47
brow42 a comment
for the developers...I noticed that my LUAv1 brute force
mutate functions do not identify any mutables in the
anniversary puzzle or the caused by the mutation filter, but
I think that was not enabled on these puzzles.
drumpeter18yrs9yrsIRC tim, i
honestly have more freedom with these mutate handfolding
puzzles.
betahelix @TimovdL
we'll post round2 with scripts/sharing next week
Aaron I'm
letting bk and beta handle these questions, they are typing
furiously next to me
frood66 ever the
optimist lol
drumpeter18yrs9yrsIRC thanks for
the aa color
TimovdL Unless you
have multiple instances, one for devprev, one for main
bk @brow42,
noted, would you mind making a feedback for that so we have
a detailed record of the problem?
brow42 alright
betahelix @brow42
and marie_s we could make the ends have an even more strict
RMSD if the
marie_s you
effectly lost the condition when you fold them
marie_s inside
betahelix Perhaps we
should repost the puzzle with that change now (letting you
load in your solutions from the past hour of course)
silverbergirc I just
tried mutate all at 0 CI, and it crashed.
TimovdL Or give
penalties if a solution invades a territory that should
remain free
disturbedxxx666 IMAGE: href="http://fold.it/portal/files/chatimg/irc_398223_1369342246.png"
rel="nofollow">http://fold.it/portal/files/chatimg/irc_398223_1369342246.png
frood66 repost
sounds good
drumpeter18yrs9yrsIRC so these
need to be exposed?
Aaron Yes
drumpeter18yrs9yrsIRC thats
ironic
betahelix @silverberg
anything odd in your log.txt?
Aaron So for the
flu puzzles, we test them by making yeast cells display the
proteins on their surface
silverbergirc Where is
that?
brow42 I did not
bring the ends in, my overall RMSD was 0.8.
TimovdL Give
penalties if packing score for those ends go up
betahelix @silverberg
search for data files:
betahelix href="http://fold.it/portal/info/faq" rel="nofollow">http://fold.it/portal/info/faq
drumpeter18yrs9yrsIRC any point
in rebuilding?
brow42 the ends
had moved about 0.5 A I think.
betahelix ok... so
nothing drastic? you weren't able to bury them in the core
or anything
brow42 I didn't
try, I tried to keep the shape close, perhaps too close.
marie_s no, but
half burying give away many freedom
marie_s we have to
test more
Madde is the
length of rubber bands measured in A?
brow42 hah! Madde
wants an authoritative answer!
Aaron the used
to visualize the protein.
TimovdL As far as
I can tell yes Madde
Madde I always
thought so, but wasn't totally sure
brow42 Ah, so the
ends have some freedom to move then, its not like they are
part of a big megamolecule?
drumpeter18yrs9yrsIRC may i ask
i question that has nothing to do with the puzzle?
Aaron So
basically both ends do things, that you don't see. However,
they can be moved a little, but folding them into the center
of the protein not the goal.
Aaron They are
like tethers
Aaron It's ok,
that they are a bit flexible, as long as the ends are free
drumpeter18yrs9yrsIRC when does
foldit for kinect come out? or is it already out?
Aaron bk/betahelix/me
are all debating right now what do about the ends
betahelix @drumpeter
of course you can ask away, we are nearing the end of our
Scientist Chat though (so if there are any final questions
for Aaron, please let us know)
porkythepundit How about
leaving them there and placing an instruction in the
introduction?
frood66 can they
not be held with constraints like cutpoints are? (modified
of course)
Aaron Our
consensus has been not to change the ends, but adding a note
on the instruction seems appropriate
brow42 please be
sure that whatever you do, you do not introduce a wiggle
locked segment in the process
Susume2 if someone
tucks the ends in it I would think it would quickly exceed
the RMSD constraint
betahelix (that is
exactly what we want to avoid, brow42
betahelix @Susume
that is what we've been trying to do for the past 5 minutes
Aaron The show
to scientist button will be out tomorrow, and can be used to
submit an free end but lowering scoring solution if you find
it
BletchleyParkirc a
<comment; next chat, please
prepare the background information so we can
<me seems more time
efficient.
katfish Noted, BP.
I can help take care of that going forward.
betahelix "Upload
for Scientists" button
porkythepundit I ike that
idea
BletchleyParkirc much
appreciated Kate.
katfish you bet
betahelix One last
question for Aaron?
drumpeter18yrs9yrsIRC what about
that paper clip thingy
silverbergirc Foldy? He
was cute.
Aaron Ok, ya'll
I'm going to get back to the bench and making flu proteins
katfish Foldy?
BletchleyParkirc will there
be a puzzel for influenza B ?
Aaron Thanks so
much for you feedback
porkythepundit Thank you
frood66 thanx
Aaron
drumpeter18yrs9yrsIRC are yall
still doing foldy?
Aaron @Bletchley:
maybe, but not for about 6 months
YoyoParis shalom
shalom
BletchleyParkirc ok, thank
you
katfish He may
come out to play again, drumpeter
betahelix href="http://fold.it/portal/node/994867" rel="nofollow">http://fold.it/portal/node/994867
Aaron The most
common flu strains are H1, H3, and Influenza B in that order
Aaron we are
moving down the list
BletchleyParkirc I'll
wikipedia the mortality rates for them
Aaron ha, that's
what I do
betahelix Ok
everyone, thanks again for joining us today!
Susume2 any
comment on next ED puzzle beta?
BletchleyParkirc thank you
for your patience.
marie_s bye
betahelix yes, I
promised that didn't I?
Aaron bye
everyone
betahelix Bye bye
Aaron!
YoyoParis bye
Aaron and THANKS
SO MUCH FOR ALL YOUR WORK!
Hanto one last
thing beta, did we ever find out what yesterday's update was
about?
betahelix The next
ED puzzle will be an exciting one, but a tough one because
Hanto all ED are
tough from MPOV
drumpeter18yrs9yrsIRC it would
help to have ss
betahelix none of
the automated methods for ED have been able to solve it.
YoyoParis ED ?
betahelix This will
make it even more exciting if you are able to solve it, of
course
betahelix (Electron
Density)
drumpeter18yrs9yrsIRC is there
anyway we can have the ss?
BletchleyParkirc Steve B
should do a video on ED
betahelix I concur
BP!!!
brow42 please
smooth the ed, or consider something where we can switch
between the scored ED and a smoothed version
YoyoParis oh thank's
, Brow42 make good cook
brow42 you're
welcome, yoyoparis
betahelix @Hanto
katfish, I believe we were going to post the description
about yesterday's update in the comments from the previous
update, right?
silverbergirc I for one
have trouble reading the ED cloud.
marie_s I cannot
fold with ED score and without relative scoring
YoyoParis I want you
like buddies
betahelix @drumpeter
do you mean ss predictions for the ED puzzle?
drumpeter18yrs9yrsIRC yes
katfish Yep,
getting that going now
YoyoParis yes
betahelix we can get
those!
brow42 relative
score coloring for ED should be bumped up in priority
Susume2 +1
betahelix as for the
relative scoring, I know we're trying to fix that but
apparently it's not trivial, I will bump that up then!
silverbergirc Ok, an
open question. Why are some of the segments darker?
YoyoParis It's my
anniversary
brow42 broken
since at least sept, so if you want anybody besides steveb
to fold it, that needs to be fixed.
marie_s the darker
cannot be mutated
brow42 apparently
steveb doesn't need fancy score colors.
betahelix got it
porkythepundit Congrats
drumpeter18yrs9yrsIRC thank tou
beta. i am lost without it. maybe up to 20 ss predictions.
silverbergirc Thanks
marie.
YoyoParis there is
no dark , only light
YoyoParis full light
betahelix ok
everyone, thanks again for joining us today. We'll add the
comment about the ends to the Flu Puzzle's comments
CFC cheers
beta
BletchleyParkirc you may
want to sanitize the log as well. Thank you for being here
katfish Thanks,
everyone!
drumpeter18yrs9yrsIRC susume,
those are non mutable
betahelix @BP yes,
sanitizing the log is a good idea
betahelix bye
everyone!
BletchleyParkirc bye !

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