Electrostatic Eesolvation Energy of Barnase Electrostatic

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Electrostatic Eesolvation Energy of Barnase Electrostatic
Comparative Binding Energy (COMBINE)
Analysis of Barnase-Barstar Interfacial Mutants
Binding features:
• High binding affinity (Kd=10-14 M)
barstar
•Polar binding interface: positive(+2e) on
BN, negative (-6e) on BS
•Hot-spots Residues at the interface
barnase
65 complexes with interfacial mutations
Barnase
Barstar
Arg59
Glu73
Lys27
Trp44
Glu80
Thr42
His102
Arg87
Arg83
Glu76
Trp38
Asp39
Asp35
Tyr29
65 complexes with different interfacial mutations
No.
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
Complex
wtwt
wtK27Awm
wtR59A
D39AR59A
wtR87A
wtH102Awm
Y29FWTWMx
Y29AWT
D35Awtwm
W38FWT
D39Awt
T42Awt
W44FWT
E76wt
E80AWT
Y29AK27AWM
D35AK27Awm
W38FK27AWM
D39AK27Awm
T42AK27Awm
E76AK27AWM
E80AK27Awm
Y29AR59A
D35AR59AWM
W38FR59A
T42AR59A
E76AR59A
E80AR59A
Y29AR83Q
D35AR83QWM
Exp. Binding delta_G
-19
-13.6
-13.8
-7.7
-13.5
-12.9
-19.1
-15.6
-14.5
-17.4
-11.3
-17.2
-19
-17.7
-18.5
-10.4
-9.5
-12.6
-10.8
-13.3
-12.3
-13.5
-10.9
-12.7
-12.8
-12.2
-14.1
-13.9
-10.7
-9.4
Desol_BN
83.29
61.78
67.68
60.52
75.58
75.93
74.54
76.86
82.35
80.2
78.3
82.07
82.54
76.34
77.67
56.34
58.45
59.29
52.85
59.23
54.36
58.31
61.75
63.45
66.82
65.87
65.73
65.04
65.36
67.83
Desol_BS
75.7
64.66
69.38
23.06
70.4
73.32
66.27
66.26
51.48
72.81
44.99
73.01
74.96
70.45
70.21
56.68
41.3
62.5
41.48
63.75
59.53
61.2
60.39
48.5
68.36
66.64
66.76
67.33
62.63
47.64
Elec_inter
-149.629
-121.787
-120.451
-45.371
-111.981
-131.979
-129.535
-131.241
-121.022
-147.522
-89.331
-142.04
-148.134
-133.19
-140.513
-104.906
-91.552
-115.126
-74.609
-118.2
-103.754
-116.631
-102.207
-100.483
-119.921
-112.196
-118.262
-118.106
-85.188
-72.423
Elect_binding_G
9.359
4.658
16.608
38.204
33.999
17.279
11.274
11.88
12.814
5.49
33.96
13.042
9.37
13.595
7.366
8.114
8.19
6.671
19.723
4.773
10.137
2.877
19.926
11.458
15.255
20.308
14.23
14.257
42.797
43.046
65 complexes with different interfacial mutations
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
61
62
63
64
65
D39AR83Q
T42AR83Q1wm
E76AR83Q
E80AR83Q
Y29AR87A
T42AR87A
E76AR87A
E80AR87A
Y29AH102AWM
Y29FH102AWMx
W38FH102AWM
D39AH102Awm
T42AH102Awm
E76AH102AWM
E80AH102AWM
D35AE73Wwm
D39AE73A
D39AE73Q
E76AE73Q
wtE73A
wtE73C
wtE73F
wtE73Q
wtE73S
wtE73Y
D35AE73Awm
D35AE73Fwm
D39AE73F
D39AR87A
E76AE73W
W38FR87A
WTE73W
WTR83Q
D39AE73W
-12.6
-12.9
-12.3
-13.3
-11
-12
-12.2
-12.9
-12.7
-13.5
-11.4
-10.1
-10.9
-11.5
-12.3
-13.3
-11.9
-11.8
-15.5
-16.7
-16.5
-16.8
-17.6
-16
-16.6
-12.6
-12.6
-11.6
-11.9
-15.5
-12
-17.4
-13.6
-12.4
55.34
66.04
63.86
68.43
70.18
72.96
69.28
72.71
69.04
69.12
75.04
70.31
74.47
71.25
74.11
97.49
86.44
98.07
100.37
91.86
97.02
104.48
104.47
93.75
96.73
95.94
103.76
95.04
68.25
94.18
75.12
97.84
67.07
91.53
42.26
68.45
67.18
69.37
61.85
68.27
66.45
68.65
62.5
63.08
71.71
43.2
70.98
68.4
70.37
51.49
44.05
44.89
71.19
70.78
73.44
76.16
75.68
71.2
73.9
48.24
52.4
44.16
44.93
71.18
69.55
75.42
70.61
44.32
-75.182
-90.987
-83.349
-96.995
-102.068
-103.662
-96.035
-107.539
-112.803
-112.538
-130.846
-80.129
-123.278
-117.52
-128.723
-141.319
-95.671
-99.043
-159.859
-166.59
-171.877
-181.322
-174.595
-168.858
-176.256
-133.672
-142.665
-96.927
-84.455
-163.989
-110.615
-179.2
-95.287
-97.266
22.416
43.506
47.686
40.802
29.963
37.568
39.696
33.82
18.736
19.669
15.908
33.379
22.171
22.128
15.757
7.661
34.825
43.918
11.704
-3.953
-1.42
-0.674
5.553
-3.913
-5.623
10.504
13.491
42.276
28.724
1.37
34.049
-5.934
42.397
38.585
Electrostatic Desolvation Free Energy Calculation
• UHBD6.1: Solving the Poisson-Boltzmann equation using a finite
difference method
bind
desol  P
desol  L
PL
Gele
 Gele
 Gele
 Eele
desol  P
Gele
PL
Eele
desol  L
Gele
PL
Eele
Electrostatic Eesolvation Energy of Barnase
R2<0.1
Electrostatic Eesolvation Energy of Barstar
R2=0.41
Electrostatic Interaction Energy between Barnase and Barstar
R2=0.63
Electrostatic Binding Free Energy
R2=0.35
Energy Decomposition to each BN-BS
residue pair
• Each complex was energy-minimized in AMBER7.0 with AMBER94 ff
• Lennard-Jones interactions were calculated for each BN-BS residue pair
(110 x 89 = 9790)
• Coulomic interactions were calculated for each BN-BS residue pair
(110 x 89 = 9790)
• Desolvation energies of BN and BS were calculated in UHBD6.1
Each complex: 19582 (=9790+9790+2) energy terms
Chemometric Analysis
• Principal Component Analysis (PCA)
• Partial Least Squares Analysis (PLS)
R
R
L
L
G  w desol
Gdesol
 w desol
Gdesol
  w ivdw uivdw   w iele uiele  C
i
Contribution of each energy term:
Importance of each residue pair
i
Contribution of translational and
rotational entropy change
Table 1. Predictive Performance of the COMBINE Model
Data
set
G
#Complexes
65
#LV
R2
Q2
SDEP
(kcal/mol)
Constant C
(kcal/mol)
4
0.65
0.57
1.67
-2.928
5
0.85
0.74
1.29
+1.63
6
0.91
0.86
0.97
+5.364
7
0.93
0.88
0.87
+6.351
Barstar
R83
R87
R59
H102
D75
K27
E73
R59vdw
H102vdw
R83vdw
K27vdw
D39
D35
G31
T42
A36
W38
E76
E80
E76vdw
Y29vdw
D39vdw
T42vdw
Normalized Coefficients at 6 LV
2
1.5
1
0.5
0
-0.5
Barnase

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