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IRENE Conference
IRENE Conference
IRENE Conference
IRENE Conference
IRENE Conference
IRENE Conference
IRENE Conference
IRENE Conference
IRENE Conference
IRENE Conference
IRENE Conference
IRENE Conference
IRENE Conference
IRENE Conference
IRENE Conference
IRENE Conference
IRENE Conference
IRENE Conference
IRENE Conference
IRENE Conference
IRENE Conference
IRENE Conference
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IRENE Conference

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

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

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  • 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  
  • 8. Future  Direc$ons   Whole  protein   COSMO  solvaFon   More  automaFzaFon   Be=er  sampling  Complete  scan  of  single  mutants  Single  -­‐>  double  -­‐>  triple  mutants   PM6  in  GAMESS   Linear  scaling  PM6   PM6/PCM  interface  AlternaFves  to  adiabaFc  mapping   Beyond  PM6:  EFMO  
  • 9. Blurring  the  boundary  between  linear  scaling  QM,   QM/MM  and  polarizable  force  fields   The  Effec@ve  Fragment  Molecular  Orbital  Method   Jan  H.  Jensen,  Casper  Steinmann,  Mikael  Wistoi  Ibsen,  Kasper  Thoie   University  of  Copenhagen   Dmitri  Fedorov   AIST,  Japan  Casper  Steinmann,  Dmitri  G.  Fedorov,  and  Jan  H.  Jensen  “ The  EffecFve  Fragment  Molecular  Orbital  Method:  A  Merger  of  the  Fragment  Molecular  Orbital  and  EffecFve  Fragment  PotenFal  Methods”    Journal  of  Physical  Chemistry  A  2010,  114,  8705-­‐8712  Casper  Steinmann,  Dmitri  G.  Fedorov,  and  Jan  H.  Jensen  “ The  EffecFve  Fragment  Molecular  Orbital  Method  for  Fragments  Connected  by  Covalent  Bonds”  PLoS  ONE,  submi=ed.  h=p://arxiv.org/abs/1202.4935   11  
  • 10. The  Effec$ve  Fragment  Molecular  Orbital  (EFMO)  method   Using  ideas  from  the  EffecFve  Fragment  PotenFal  (EFP)   and  the  Fragment  Molecular  Orbital  (FMO)  method     12  
  • 11. The  Effec$ve  Fragment  Molecular  Orbital  (EFMO)  method   (Using  ideas  from  the  EffecFve  Fragment  PotenFal  (EFP)  method)   Monomer  SCF  in  the   gas  phase   Extract  mulFpoles  and  dipole  polarizability   13  
  • 12. The  Effec$ve  Fragment  Molecular  Orbital  (EFMO)  method   (Using  ideas  from  the  EffecFve  Fragment  PotenFal  (EFP)  method)  Many-­‐body  polariza$on   Computed  classically   using  induced  dipoles   for  enFre  system   14  
  • 13. The  Effec$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  
  • 14. The  Effec$ve  Fragment  Molecular  Orbital  (EFMO)  method   (Using  ideas  from  the  EffecFve  Fragment  PotenFal  (EFP)  method)  Coulomb  effects  Computed  using  staFc  mulFpoles   16  
  • 15. MP2  (DFT  doesn’t  scale  well)   +  0   17  
  • 16. Covalent  Fragmenta$on  (ElectrostaFc  screening  crucial)   18  
  • 17. 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  
  • 18. QM/”MM”   PCM  Large  parts  of  MM  region     oien    frozen     =   Requires  only  monomer     gas  phase  calculaFons   for  that  region   =   Very  fast   20  
  • 19. To  Do  Flexible  EFP/Polarizable  “Force  Field”   covalent dimers ∑ (E ) NE 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  
  • 20. Funding:    EU  (IRENE  collab  program)   Thank  You!   Ques$ons?   Slides  at:  h=p://Fnyurl.com/bsqbojf   22  

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