slides for 2016 Gordon Research Conference in Computational Chemistry

1. Can semiempirical methods be used for high throughput screening?*
(for enzyme mutants)
Jan H. Jensen, University of Copenhagen
Feel free to tweet, record, …
#CompChemGRC
*Dunno yet, trying to find out
Here’s a status report
@janhjensen
1

2. An early attempt
Turning a lipase into a amidase
Verdict: so-so
Only PM6 predicts correct mechanism
Hediger PLOS ONE 2013
Hediger PeerJ 2013
MOZYME in MOPAC
2
1 mutant per core per ~24-32 hrs

3. An early attempt
Turning a lipase into a amidase
Verdict: no mutants with high amidase activity
👍 👎
Hediger PLOS ONE 2013
Hediger PeerJ 2013a
👍
👎
High throughput screening identifies potentially interesting mutants for further study
3

4. Optimizing a xylanase for synthetic substrate
Vedict: ?? Hediger PeerJ 2013b
All possible
single mutants
Select
double mutants
4

5. Need PM6 in “open source” program to proceed
Implementing PM6 in GAMESS
PM6 & DFTB now in AmberTools
PM6 up to Fluorine ✔
PM6/PCM up to F ✔
PM6-D3H+ ✔
PM6 for > F
Linear scaling PM6
QM/MM PM6
Kromann unpublished
Svendsen PLOS ONE 2013
Kromann PeerJ 2014
Linear scaling DFTB ✔
DFTB/PCM ✔
QM/MM DFTB
Nishimoto CPL 2015
Nishimoto JPCA 2016
5

6. How accurate are PM6 and DFTB for enzyme barrier heights?
Verdict: 4(ish) out of 5 for both methods
Kromann, Cui PeerJ 2016
Himo: B3LYP/6-311+G(2d,2p)[LANL2DZ]//B3LYP/6-31G(d,p)
PM6 ✔
DFTB ✔PM6 ✔
DFTB ✘
PM6 ✘
DFTB ✔
PM6 ✔
DFTB ✔
PM6 ✔
DFTB ✔
6

7. Can semiempirical methods be used for high throughput screening?
pKa prediction
Verdict: OK(ish) Jensen Arxiv 2015
Kromann PeerJ 2016
Amines
7

8. Can semiempirical methods be used for high throughput screening?
pKa prediction
Jensen arXiv 2015
Kromann PeerJ Preprints 2016
ChemAxon
Et3N
Ref a
Ref b
Experiment
9.1
-0.2
0.1
0.7
4.2
Ref a
Ref b
CPU time
~3 min/core
/conformer
PM6/COSMO
8

9. Can semiempirical methods be used for high throughput screening?
Open questions/challenges
How to routinely handle 1000s of molecules?
(I need to learn cheminformatics)
Efficient conformer search for proteins?
Automatic & robust TS search?
Improve accuracy by machine learning?
machine learning + (DLNPO) CCSD(T) = new semiempirical methods?
Multipurpose or problem-specific methods?
Experimental validation/competition
(Must be better (& faster) than experimental high throughput)
9
Guallar
Zimmerman, +…
von Lilienfeld
Reiher