Successfully reported this slideshow.
We use your LinkedIn profile and activity data to personalize ads and to show you more relevant ads. You can change your ad preferences anytime.

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

578 views

Published on

slides for 2016 Gordon Research Conference in Computational Chemistry

Published in: Science
  • Be the first to comment

  • Be the first to like this

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 F Linear scaling PM6 QM/MM PM6 Kromann unpublished Svendsen PLOS ONE 2013 Kromann PeerJ 2014 Linear scaling DFTB ✔ DFTB/PCM ✔ QM/MM DFTB Nishimoto CPL 2015 Nishimoto JPCA 2016 5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

×