Can	semiempirical methods	be	used	for	high	throughput	screening?*
(for	enzyme	mutants)
Jan	H.	Jensen,	University	of	Copenh...
An	early	attempt
Turning	a	lipase	into	a	amidase
Verdict:	so-so
Only	PM6	predicts	correct	mechanism
Hediger PLOS	ONE 2013
...
An	early	attempt
Turning	a	lipase	into	a	amidase
Verdict:	no	mutants	with	high	amidase	activity
👍 👎
Hediger PLOS	ONE 2013
...
Optimizing	a	xylanase	for	synthetic	substrate
Vedict:	?? Hediger PeerJ 2013b
All	possible
single	mutants
Select
double	mut...
Need	PM6	in	“open	source”	program	to	proceed
Implementing	PM6	in	GAMESS
PM6	&	DFTB	now	in	AmberTools
PM6	up	to	Fluorine	✔
...
How	accurate	are	PM6	and	DFTB	for	enzyme	barrier	heights?
Verdict:	4(ish)	out	of	5	for	both	methods
Kromann,	Cui	PeerJ 201...
Can	semiempirical methods	be	used	for	high	throughput	screening?
pKa prediction
Verdict:	OK(ish) Jensen	Arxiv 2015
Kromann...
Can	semiempirical methods	be	used	for	high	throughput	screening?
pKa prediction
Jensen	arXiv 2015
Kromann PeerJ Preprints	...
Can	semiempirical methods	be	used	for	high	throughput	screening?
Open	questions/challenges
How	to	routinely handle	1000s	o...
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Can semiempirical methods be used for high throughput screening (for enzyme mutants)?

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slides for 2016 Gordon Research Conference in Computational Chemistry

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Can semiempirical methods be used for high throughput screening (for enzyme mutants)?

  1. 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. 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. 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. 4. Optimizing a xylanase for synthetic substrate Vedict: ?? Hediger PeerJ 2013b All possible single mutants Select double mutants 4
  5. 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. 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. 7. Can semiempirical methods be used for high throughput screening? pKa prediction Verdict: OK(ish) Jensen Arxiv 2015 Kromann PeerJ 2016 Amines 7
  8. 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. 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

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