AN APPROACH TO SEMI FLEXIBLE
DOCKING: A case study of the enzymatic
reaction catalysed by terpenoid cyclases
Vladimir Sobolev
Weizmann Institute of Science
DIMACS, 13 June 2005
vladimir.sobolev@weizmann.ac.il
AN APPROACH TO SEMI FLEXIBLE
DOCKING: A case study of the enzymatic
reaction catalysed by terpenoid cyclases
1. Approach to molecular docking and
definition of surface complementarity
2. Modeling first two steps of enzymatic
reaction catalysed by terpenoid cyclases
AN APPROACH TO SEMI FLEXIBLE
DOCKING: A case study of the enzymatic
reaction catalysed by terpenoid cyclases
1. Approach to molecular docking and
definition of surface complementarity
2. Modeling first two steps of enzymatic
reaction catalysed by terpenoid cyclases
Relevant Questions for Docking
Where is the binding site located?
What is the ligand orientation?
Two Major Algorithmic Issues
in Molecular Docking:
1. Scoring function
2. Search procedure
Complementarity Function
for molecular docking
CF = Sl - Si - Er
Sl = surface area of legitimate atomic contacts
Si = surface area of illegitimate atomic contacts
Er = a repulsion term
Definition of Contact Surface Between Atoms
Ra,Rb ~ 1.5-2.0 Å;
Rw = 1.4 Å
• contact surface of atom A with B is
the surface area of sphere A that
penetrates sphere B.
Thus, contact appears
from Rab ~ 6 Å
Definition of Contact Surface Between Atoms
In both cases Rab is the same, while in
second case there is no contact between
atoms A and B
Atomic Classes
I
Hydrophilic
N or O that donate or accept a hydrogen bond (e.g., O of OH
group of Ser or Thr)
II
Acceptor
N or O that only accept a hydrogen bond (e.g., O of peptide
group)
III
Donor
N that only donates a hydrogen bond (e.g., N of peptide group)
IV
Hydrophobic
Cl, Br, I and C atoms not in aromatic rings and not covalently
bonded to N or O
V
Aromatic
C atoms in aromatic rings
VI
Neutral
S, F, P, and metal atoms; C atoms covalently bonded to one or
more atoms of
class I or two or more atoms of class II or III
VII Neutral-donor C atoms that are covalently bonded to only one atom of class
III
VIII Neut.-acceptor C atoms that are covalently bonded to only one atom of class
II
Legitimacy (for each pair of contacts)
Atomic class
I
II
III
IV
V
VI
VII
VIII
Hydrophilic
Acceptor
Donor
Hydrophobic
Aromatic
Neutral
Neutral-donor
Neutral-acceptor
I
II
III IV
V VI VII VIII
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-
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+
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-
Complementarity Function
for molecular docking
CF = Sl - Si - Er
Sl = surface area of legitimate atomic contacts
Si = surface area of illegitimate atomic contacts
Er = a repulsion term
Flow Chart of LIGIN Program
Input coordinates, size of search cube ,
number of initial ligand positions (N), and
number of best positions kept (M)
n=1
Generate random ligand position
and orientation in the search cube
Maximize complementarity function
(CF)
.
n = n+1
Keep not more than M best maxima
Does n equal N?
No
Yes
Optimize H-bond lengths for
every M structure obtained
Cluster maxima
Satisfactory CF
position found?
No
Yes
Calculate and list contacts for the
position with highest complementarity
Calculate and list normalized complementarity
(CF) following atom substitution
Neglect steric clash
for a user defined
number of residues
Critical Assessment of
Techniques for Protein
Structure Prediction
Our Results
http://sgedg.weizmann.ac.il/casp2
AN APPROACH TO SEMI FLEXIBLE
DOCKING: A case study of the enzymatic
reaction catalysed by terpenoid cyclases
1. Approach to molecular docking and
definition of surface complementarity
2. Modeling first two steps of enzymatic
reaction catalysed by terpenoid cyclases
Chemical scheme of the substrate (farmecyl
diphosphate (FFP)
8
6
8
6
7
7
9
9
5
5
4
2
14
10
13
3
1
OPP
12
11
15
3
10
2
4
13
1
11
14
12
Terpenoid cyclases
may produce a large
number of products
from a single
substrate.
Steele et al., 1998
Chemical scheme of the substrate (farmecyl
diphosphate (FFP)
8
6
8
6
7
7
9
9
5
5
4
2
14
10
13
3
1
OPP
12
11
15
3
10
2
4
13
1
11
14
12
Flowchart describing semi flexible docking
Results of the semi flexible docking
for the first stage
Complementarity
score (Å2)
Free dihedral angles
PA-O5A
O5A-C1
C1-C2
C3-C4
C4-C5
C5-C6
C7-C8
C8-C9
C9-C10
1
84.6
-121.7
173.7
-107.7
111.4
-35.9
-124.3
-103.9
32.6
541.3
2
14.9
183.3
-123.1
2.5
61.7
59.6
41.5
-126
36.9
532.6
3
90
-118.2
191.2
-122.8
114
-43.9
117.4
109.1
29
524.2
4
84.4
-119.2
178.1
-117.4
105.3
-29.9
-102.2
-107.1
33.4
522.6
5
39.6
180.6
-124
116.8
-116.5
20.9
123
80.6
32.5
521.7
6
102.6
-142.3
133.4
-23.4
115.5
-115.9
-118.1
-62.4
-24.3
518.5
7
89.9
171.6
130.5
152.5
-64.6
-24.5
245.6
-126.8
37.9
516.3
8
46.5
178.1
-130.3
30.3
-30.9
129.6
182.6
121.4
-10.5
516.0
9
43.3
182.5
-126.5
116.2
-107
22.7
186
-53.2
195.7
516.0
10
92.3
-125.5
156.1
-60.2
102.4
-102.7
-77
-137.2
26.9
515.9
11
99.9
-130.7
131.3
-29.6
105.1
187.1
-163.9
68.5
40.2
515.5
12
86.2
-121.4
175.1
-124.5
117.9
-26.7
-107.5
-61.1
-30.3
515.4
13
88.7
-122.1
172.1
-110.9
108.2
-58.9
191.2
70.9
35
514.9
14
94.1
-129.3
133.7
-40.3
110.7
185.5
-12.2
-77
-21
514.4
15
87.5
-117.5
159.9
-97.4
105.3
-117.7
-5.8
-102.2
39.9
514.1
16
88.7
-124.3
168.8
-123
118.8
-43.9
-104.8
-40.8
-98.2
513.9
17
102
-145.8
133.7
-30.5
115.3
-104.2
126.2
123.1
-23.7
513.9
18
100.9
-147.6
140.8
-31
108
-40.4
163.4
-95.4
48.1
511.8
Residues forming contacts with the leading
structure
Res.
Dist Sur
.
f
Å Å2
Res.
Dist Surf
.
Å2
Å
Arg264
Trp273
Ile294
3.2
3.6
3.7
32
56
29
Tyr404
Leu407
Cys440
3.4
3.9
3.9
29
16
22
Ile297
Ser298
Asp301
4.3
4.1
3.0
16
23
28
Ile515
Val516
Tyr520
4.1
4.8
3.1
10
10
43
Asp305
Thr402
Thr403
2.6
3.9
4.1
13
21
18
Asp525
Tyr527
2.5
3.9
34
48
Docking prediction for WT pocket and three
mutants. Blue - predicted structure; green experimental one
WT
V516G
V440G
Y520G
Contribution for the complementarity
function of all groups of 4 adjacent
carbons.
Ord
er
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
Carbon atoms
(see Fig. 3)
C 10 C 11 C1 2 C1 5
C9
C 10 C 11 C1 2
C 3 C 4 C1 4 C5
C 6 C 7 C8 C9
C 3 C 4 C5 C6
C 4 C 5 C6 C7
C 5 C 6 C7 C8
C 9 C 10 C1 1 C1 5
C 2 C 3 C4 C1 4
C 1 C 2 C3 C1 4
C 7 C 8 C9 C1 0
C 8 C 9 C1 0 C1 1
C 5 C 6 C7 C1 3
C 2 C 3 C4 C5
C 6 C 7 C8 C1 3
C 7 C 8 C1 3 C9
C 1 C 2 C3 C4
Complemen
tarity sum
1 16 . 00
1 14 . 00
7
9
5
3
4
1 02 . 00
85 . 00
81 . 00
81 . 00
80 . 00
78 . 00
77 . 00
72 . 00
69 . 00
69 . 00
53 . 00
51 . 00
50 . 00
49 . 00
44 . 00
8
6
2
14
13
1
OPP
10
12
11
15
Contribution for the complementarity
function of all groups of 4 adjacent carbons.
N
Carbon Atoms
COMPLEMENTARITY
1
C10 C11 C12 C15
116
2
C9 C10 C11 C12
114
3
C3 C4 C14 C5
102
4
C6 C7 C8 C9
85
5
C3 C4 C5 C6
81
6
C4 C5 C6 C7
81
7
C5 C6 C7 C8
80
8
C9 C10 C11 C15
78
9
C2 C3 C4 C14
77
10
C7 C8 C9 C10
69
11
C8 C9 C10 C11
69
12
C5 C6 C7 C13
53
13
C2 C3 C4 C5
51
14
C6 C7 C8 C13
50
15
C7 C8 C13 C9
49
8
6
7
9
5
3
4
2
14
13
1
OPP
10
12
11
15
Scheme for the prediction of the
second step of the reaction
8
6
7
9
5
13
3
4
2
14
1+
10
12
11
15
Analysis of the results of the “second
stage” reaction model
K
N
Compl
.
Max.
Compl.
Contacts with (C1)
Cluster
1
107
412
457
Thr402
a
2
96
459
508
Tyr520, Asp444
b
3
16
541
555
Tyr404, Thr403, Thr402
c
3
21
534
555
Tyr520, Asp444
d
3
85
519
555
Trp273
e
4
16
601
615
Trp273
f
5
10
677
697
Trp273
e
5
34
661
697
Trp273
g
5
52
655
697
Tyr404
h
7
2
819
833
Trp273
e
9
1
990
990
Trp273
e
List of super-groups clustered according to
the interaction with carbocation C1
Super-grope Group
number
letters
1
e, f, g
Contacts with C1
2
b, d
3
c, h
4
a
Tyr520, Asp44,
Asp525
Tyr404, Thr403,
Thr402
Thr402
Trp273
Two candidates for amino acids involved in
stabilising the reaction intermediate
Summary
1. Docking algorithm was described
2. First two steps of enzymatic
reaction catalysed by terpenoid
cyclases were modeled. There is
already experimental data
confirming correctness of the first
step model. While modeling second
step in the large extent speculative
ACKNOWLEDGMENTS
Meir Edelman (WIS)
Eran Eyal (WIS)
Gert Vriend (EMBL)
Rebecca Wade (EMBL)
AN APPROACH TO SEMI FLEXIBLE
DOCKING: A case study of the enzymatic
reaction catalysed by terpenoid cyclases
Vladimir Sobolev
Weizmann Institute of Science
DIMACS Workshop, 12 June 2005
vladimir.sobolev@weizmann.ac.il