Recording of the talk: http://proteinsandwavefunctions.blogspot.com/2012/05/my-talk-at-irene-meeting.html

1. Industrial
Strength
QM/MM:
Computa8onal
high
throughput
screening
of
enzyme
ac8vity
in
enzyme
mutants
Jan
H.
Jensen,
Mar$n
Hediger,
Luca
De
Vico,
Kasper
Primdal,
Allan
Svendsen,
Werner
Besenma=er
Department
of
Chemistry
University
of
Copenhagen
Slides
at:
h=p://Fnyurl.com/bsqbojf
MarFn
R.
Hediger,
Luca
De
Vico,
Allan
Svendsen,
Werner
Besenma=er,
Jan
H.
Jensen
“A
ComputaFonal
Methodology
to
Screen
AcFviFes
of
Enzyme
Variants”
PLoS
ONE,
submi=ed.
h=p://arxiv.org/abs/1203.2950

2. Slides
at:
h=p://Fnyurl.com/bsqbojf
Industrial
enzyme
design
High-­‐through
put
screening
of
100s
of
mutants
IdenFfies
promising
candidates
for
further
study
ComputaFonal
predicFon:
Homology
modeling
QSAR
(QM
or
QM/MM
too
slow
and
lacks
automaFon)
IdenFfies
promising
candidates
for
further
study
Further
study:
20-­‐50
mutants
Goal
Automated
predicFon
of
barrier
height
for
enzymaFc
reacFon
within
24
hr
using
<
10
cores
IdenFfies
promising
candidates
for
further
study

3. Methods
PM6
implemented
in
Mopac2009
(MOZYME)
Automated
mutant
builder
(PYMOL)
Barrier
from
adiabaFc
mapping
Applica$on
Increase
amidase
acFvity
in
an
estarase
(CalB)
MarFn
R.
Hediger,
Luca
De
Vico,
Allan
Svendsen,
Werner
Besenma=er,
Jan
H.
Jensen
“A
ComputaFonal
Methodology
to
Screen
AcFviFes
of
Enzyme
Variants”
PLoS
ONE,
submi=ed.

4. PM6
is
good
enough

5. PM6
and
MOZYME
MOZYME
=
PM6
computed
with
MOZYME
PM6
=
PM6//MOZYME
MOZYMEReortho
=
MOZYME//MOZYME

6. PM6/MOZYME
is
fast
enough
55
aa
MOPAC2009
No
parallelized

7. PM6/MOZYME
is
fast
enough
OpFmizaFon
Single
point

10. Future
Direc$ons
Whole
protein
COSMO
solvaFon
More
automaFzaFon
Be=er
sampling
Complete
scan
of
single
mutants
Single
-­‐>
double
-­‐>
triple
mutants
PM6
in
GAMESS
Linear
scaling
PM6
PM6/PCM
interface
AlternaFves
to
adiabaFc
mapping
Beyond
PM6:
EFMO

11. Blurring
the
boundary
between
linear
scaling
QM,
QM/MM
and
polarizable
force
fields
The
Effec@ve
Fragment
Molecular
Orbital
Method
Jan
H.
Jensen,
Casper
Steinmann,
Mikael
Wistoi
Ibsen,
Kasper
Thoie
University
of
Copenhagen
Dmitri
Fedorov
AIST,
Japan
Casper
Steinmann,
Dmitri
G.
Fedorov,
and
Jan
H.
Jensen
“ The
EffecFve
Fragment
Molecular
Orbital
Method:
A
Merger
of
the
Fragment
Molecular
Orbital
and
EffecFve
Fragment
PotenFal
Methods”
Journal
of
Physical
Chemistry
A
2010,
114,
8705-­‐8712
Casper
Steinmann,
Dmitri
G.
Fedorov,
and
Jan
H.
Jensen
“ The
EffecFve
Fragment
Molecular
Orbital
Method
for
Fragments
Connected
by
Covalent
Bonds”
PLoS
ONE,
submi=ed.
h=p://arxiv.org/abs/1202.4935
11

12. The
Effec$ve
Fragment
Molecular
Orbital
(EFMO)
method
Using
ideas
from
the
EffecFve
Fragment
PotenFal
(EFP)
and
the
Fragment
Molecular
Orbital
(FMO)
method
12

13. The
Effec$ve
Fragment
Molecular
Orbital
(EFMO)
method
(Using
ideas
from
the
EffecFve
Fragment
PotenFal
(EFP)
method)
Monomer
SCF
in
the
gas
phase
Extract
mulFpoles
and
dipole
polarizability
13

14. The
Effec$ve
Fragment
Molecular
Orbital
(EFMO)
method
(Using
ideas
from
the
EffecFve
Fragment
PotenFal
(EFP)
method)
Many-­‐body
polariza$on
Computed
classically
using
induced
dipoles
for
enFre
system
14

15. The
Effec$ve
Fragment
Molecular
Orbital
(EFMO)
method
(Using
ideas
from
the
EffecFve
Fragment
PotenFal
(EFP)
method)
Coulomb
and
Non-­‐Coulomb
effects
dimer
SCF
in
the
gas
phase
15

16. The
Effec$ve
Fragment
Molecular
Orbital
(EFMO)
method
(Using
ideas
from
the
EffecFve
Fragment
PotenFal
(EFP)
method)
Coulomb
effects
Computed
using
staFc
mulFpoles
16

17. MP2
(DFT
doesn’t
scale
well)
+
0
17

18. Covalent
Fragmenta$on
(ElectrostaFc
screening
crucial)
18

19. Implemented
in
GAMESS
With
gradients
Trp
cage
(20
residues)
2
residues/fragment
EFMO
FMO2
Error
in
energy
-­‐4.3
6.4
kcal/mol
MP2/6-­‐31G(d)
gradient
314
409
minutes
20
cores
(most
Fme
spent
in
MP2
dimers)
19

20. QM/”MM”
PCM
Large
parts
of
MM
region
oien
frozen
=
Requires
only
monomer
gas
phase
calculaFons
for
that
region
=
Very
fast
20

21. To
Do
Flexible
EFP/Polarizable
“Force
Field”
covalent
dimers
∑ (E )
N
E EFMO = ∑ EI0 + 0
IJ − EI0 − EJ − EIJ
0 POL
I IJ
( )
N
+ ∑ EIJ + EIJ /CT + EIJ + Etot
ES XR Disp POL
IJ
Important
miscellanea
EFMO
GUI:
FRAGIT
(Mikael
Ibsen)
TS
search
algorithms
(Kasper
Thoie)
21

22. Funding:
EU
(IRENE
collab
program)
Thank
You!
Ques$ons?
Slides
at:
h=p://Fnyurl.com/bsqbojf
22