Modeling	  Chemical	  	  Reac0ons	    (in	  Enzyme	  Ac0ve	  Sites)	                  Jan	  H.	  Jensen	           Departm...
DOI:	  10.1021/jo800706y	  
We	  measure	  the	  rate	  (constant)	  But	  compute	  the	  ac0va0on	  free	  energy	                      d[4] d[4p]  ...
To	  compute	  the	  rate	  constant	  we	  need	  to	  find	  	                     the	  transi0on	  state	  Image:	  h4p...
Since	  bonds	  are	  broken/formed	  we	  must	  use	  	                                                quantum	  mechani...
The	  free	  energy	  has	  two	  contribuGons:	                                     PotenGal	  (electronic)	  energy	  an...
Approximate	  TS	  as	  maximum	  on	  Reac0on	  Coordinate	  scan	                                     the	  Poten0al	  E...
Approximate	  TS	  can	  then	  serve	  as	  a	  starGng	  point	  for	  finding	                                          ...
Once	  the	  real	  transiGon	  state	  is	  found	  the	  vibraGonal	  free	  energy	  can	  be	  calculated	  to	  yield...
Building	  a	  TransiGon	  State:	  The	  movie	  h4p://molecularmodelingbasics.blogspot.com/2009/06/building-­‐transiGon-...
Modeling	  Chemical	  Reac0ons	  in	  	                                                              Enzyme	  Ac0ve	  Site...
image:	  10.1080/01442350903495417	                                            One	  opGon	  is	  to	  make	  a	  small	  ...
image:	  10.1080/01442350903495417	                                             Another	  opGon	  is	  QM/MM	             ...
Ques0ons	  Now?	                                      Ques0ons	  Later?	                                   Leave	  a	  com...
Upcoming SlideShare
Loading in...5
×

Modeling Chemical Reactions (in Enzyme Active Sites)

807

Published on

Published in: Technology
0 Comments
0 Likes
Statistics
Notes
  • Be the first to comment

  • Be the first to like this

No Downloads
Views
Total Views
807
On Slideshare
0
From Embeds
0
Number of Embeds
24
Actions
Shares
0
Downloads
14
Comments
0
Likes
0
Embeds 0
No embeds

No notes for slide

Modeling Chemical Reactions (in Enzyme Active Sites)

  1. 1. Modeling  Chemical    Reac0ons   (in  Enzyme  Ac0ve  Sites)   Jan  H.  Jensen   Department  of  Chemistry   University  of  Copenhagen   h4p://propka.ki.ku.dk/~jhjensen  
  2. 2. DOI:  10.1021/jo800706y  
  3. 3. We  measure  the  rate  (constant)  But  compute  the  ac0va0on  free  energy   d[4] d[4p] − = = k[4] dt dt 0.69 t1/2 = k The  connecGon  is  Transi0on  State  Theory   k≈ kBT − ΔG ≠ / RT h e ( 10 -1 −1 = 2.1 × 10 s K T ⋅ e − ΔG ≠ / RT ) ( k ≈ 10 s 10 13 -1 ) − ΔG ≠ /1.4 (room  T,  ΔG  in  kcal/mol)  
  4. 4. To  compute  the  rate  constant  we  need  to  find     the  transi0on  state  Image:  h4p://en.wikipedia.org/wiki/TransiGon_state_theory  
  5. 5. Since  bonds  are  broken/formed  we  must  use     quantum  mechanics  to  find  the  TS   (methods  like  B3LYP/6-­‐31G(d)  and  PM3)  Source:  Patrick  Rydberg   Finding  the  TS  is  much  trickier  than  finding  the     reactant  and  product    (minima)  structures   Finding  minima:  minimize  E  along  all  degrees  of  freedom   Finding  TS:  maximize  E  along  one*  degree  of  freedom  and  minimize  along  rest   *but  which  one?   h4p://en.wikipedia.org/wiki/Saddle_point  
  6. 6. The  free  energy  has  two  contribuGons:   PotenGal  (electronic)  energy  and  vibraGonal  free  energy   Approximate  TS  as  maximum  on  Minimum  (PotenGal)  Energy  Path  (MEP)   G X ≈ Eele + Gvib X XPoten0al  energy   E  
  7. 7. Approximate  TS  as  maximum  on  Reac0on  Coordinate  scan   the  Poten0al  Energy  Surface  (PES)     G X ≈ Eele + Gvib X XPoten0al  energy   E   O-­‐C  Distance   O-­‐C  distance  is  kept  fixed  during  energy  minimizaGon  
  8. 8. Approximate  TS  can  then  serve  as  a  starGng  point  for  finding   the  real  transi0on  state   This  requires  an  (expensive)  frequency  calcula0on   G X ≈ Eele + Gvib X XPoten0al  energy   E  
  9. 9. Once  the  real  transiGon  state  is  found  the  vibraGonal  free  energy  can  be  calculated  to  yield  the  ac0va0on  free  energy   This  requires  another  (expensive)  frequency  calculaGon   G X ≈ Eele + Gvib X X
  10. 10. Building  a  TransiGon  State:  The  movie  h4p://molecularmodelingbasics.blogspot.com/2009/06/building-­‐transiGon-­‐state.html   h4p://molecularmodelingbasics.blogspot.com/search/label/transiGon%20state  
  11. 11. Modeling  Chemical  Reac0ons  in     Enzyme  Ac0ve  Sites   Enzymes  are  too  large  to  be  treated   quantum  mechanically  image:  10.1080/01442350903495417   Source:  Patrick   Rydberg   Image:  10.1021/jp805137x  
  12. 12. image:  10.1080/01442350903495417   One  opGon  is  to  make  a  small  (gas  phase)   model  of  the  acGve  site   Problems:   Key  interacGons  missing   System  is  too  floppy   Can  by  fixed  by  going  to  larger  models   but  expensive   Image:   10.1021/jp805137x  
  13. 13. image:  10.1080/01442350903495417   Another  opGon  is  QM/MM   Red:  QM  region   Yellow  &  Green:  MM   Problems:   QM/MM  Boundary   Set-­‐up  is  difficult   Schrodinger’s  QM/MM:  Qsite   Source:   10.1021/jp805137x  
  14. 14. Ques0ons  Now?   Ques0ons  Later?   Leave  a  comment  on  h4p://proteinsandwavefuncGons.blogspot.com/2011/02/modeling-­‐chemical-­‐reacGons-­‐in-­‐enzyme.html  
  1. A particular slide catching your eye?

    Clipping is a handy way to collect important slides you want to go back to later.

×