BIOINORGANIC CHEMISTRY A Short Course Second Edition

368 IRON-CONTAINING PROTEINS AND ENZYMES

and water molecules in the distal pocket of their starting material, intermedi-
ate ( 5a ) in Figure 7.14 , and intermediate ( 1 ) in Figure 7.16. Data for the start-
ing material intermediate were taken from the Schlichting PDB: 1DZ8
structure, assumed by those authors to be the FeIII−O− 2 moiety.^35 Shaik and
co - workers believed that the most realistic model for their calculations (96 -
atom Model E in reference 48 ) contained the iron – porphyrin ligand system
with thiolate axial ligand (proximal) and dioxygen as the distal ligand. The
carboxylic acid groups of asp251 and glu366 were used as proton sources
(eliminating the hydroxyl group of thr252 as a proton source for any part of
the process). The amino acid residues asp251 and thr252 with their connecting
peptide bond were important in holding a water molecule, water 901 in PDB:
1DZ8, in place (see Figure 7.13 ). Acetic acid was used to model glu366. Five
water molecules, W 901 , W 902 , W 523 , W 566 , and W 687 , formed a water channel con-
necting glu366 through thr252 and asp251 to the distal peroxo ligand, complet-
ing the model. The starting point of calculation was the structure of ( 2 ), Cpd
0, obtained by protonation of ( 1 ) via the asp251 – W 901 – thr252 channel as sug-
gested by experimental data^49 and molecular dynamics (MD) simulations.^50 In
the Cpd 0, ( 2 ) model, asp251 has been rotated from its hydrogen - bonded posi-
tion in the crystal structure (PDB: 1DZ8) as a starting point in investigating
O – O bond scission, to get from Cpd 0, ( 2 ) to Cpd I, ( 3 ). A glu366 – water – thr252
network is established for a subsequent protonation of Cpd 0. However, this
does not lead directly to Cpd I but to a “ surprise ” species, ( 2 ) prot , a ferric
complex of water – oxide (Fe – O – OH 2 ) (see Figure 7.16 ). The authors fi nd that
( 2 ) prot is a genuine minimum energy species in their calculations and also that
Cpd 0 and Cpd I are fairly close to each other energetically. Continuing with
QM/MM calculations, Shaik and co - workers confi rm that Cpd 0 and Cpd I are
close in energy whereas ( 2 ) prot is less stable by 24 – 33 kcal/mol. They believe
that more QM(DFT)/MM sampling is needed to confi rm these fi ndings.

Figure 7.16 Pathway to cytochrome P450 Compound I. (Adapted with permission
from Scheme 1 of reference 48. Copyright 2005 American Chemical Society.)

FeIV

O

S

Cys

( 3 ), Cpd I

H 2 O

H+

FeIII

OOH^2

S

Cys

( 2 )prot

FeIII

OO

S

Cys

2 -

porphyrin

( 1 )

FeIII

OOH

−

S

Cys

( 2 ), Cpd 0

H+

peroxoferric hydroperoxoferric,

compound 0

oxoferryl,

compound I

protonated compound 0,

calculated