Electrostatic Interactions Between CD46(SCR1-2) and Ad11k-Ad21k
Transcript of Electrostatic Interactions Between CD46(SCR1-2) and Ad11k-Ad21k
![Page 1: Electrostatic Interactions Between CD46(SCR1-2) and Ad11k-Ad21k](https://reader031.fdocuments.in/reader031/viewer/2022011722/58ee07801a28ab7d4a8b46d5/html5/thumbnails/1.jpg)
Electrostatic Interactions Between Complement Regulator
CD46(SCR1-2) and Adenovirus Ad11/Ad21 Fiber Protein Knob
Carl ChenUC Riverside
Bioengineering
![Page 2: Electrostatic Interactions Between CD46(SCR1-2) and Ad11k-Ad21k](https://reader031.fdocuments.in/reader031/viewer/2022011722/58ee07801a28ab7d4a8b46d5/html5/thumbnails/2.jpg)
Motivation
• Adenoviruses target several systems in the body, including the respiratory and kidney areas.
• There are no direct antiviral treatments for adenoviruses due to the wide range of symptoms.
Persson, et al. Adenovirus type 11 binding alters the conformation of its receptor CD46. 2007
![Page 3: Electrostatic Interactions Between CD46(SCR1-2) and Ad11k-Ad21k](https://reader031.fdocuments.in/reader031/viewer/2022011722/58ee07801a28ab7d4a8b46d5/html5/thumbnails/3.jpg)
Background
• Over 50 serotypes of adenovirus. Ad11 and Ad21 are subtypes of type B.
• Viral globular knob binds to 2 SCR domains of CD46 to infect a variety of cells.
SCR-1 SCR-2 SCR-3 SCR-4
CD46
Ad11k or Ad21kP1
P2
Persson, et al. Structure of the extracellular portion of CD46 provides insights into its interactions. 2010
![Page 4: Electrostatic Interactions Between CD46(SCR1-2) and Ad11k-Ad21k](https://reader031.fdocuments.in/reader031/viewer/2022011722/58ee07801a28ab7d4a8b46d5/html5/thumbnails/4.jpg)
Trimer of Trimers
P1
P3 P2
SCR-1
SCR-1
SCR-1
SCR-2SCR-2
SCR-2
Persson, et al. Structure of the extracellular portion of CD46 provides insights into its interactions. 2010
![Page 5: Electrostatic Interactions Between CD46(SCR1-2) and Ad11k-Ad21k](https://reader031.fdocuments.in/reader031/viewer/2022011722/58ee07801a28ab7d4a8b46d5/html5/thumbnails/5.jpg)
CD46(SCR1-2)-Ad11k
CD46
Ad11k
SCR-1 SCR-2
P1 = chain AP2 = chain E
Interface
Petteren, et al, “UCSF Chimera”, 2004
![Page 6: Electrostatic Interactions Between CD46(SCR1-2) and Ad11k-Ad21k](https://reader031.fdocuments.in/reader031/viewer/2022011722/58ee07801a28ab7d4a8b46d5/html5/thumbnails/6.jpg)
CD46(SCR1-2)-Ad21k
CD46
SCR-1 SCR-2
P1 = chain B
P2 = chain C
Interface
Ad21k
Petteren, et al, “UCSF Chimera”, 2004
![Page 7: Electrostatic Interactions Between CD46(SCR1-2) and Ad11k-Ad21k](https://reader031.fdocuments.in/reader031/viewer/2022011722/58ee07801a28ab7d4a8b46d5/html5/thumbnails/7.jpg)
What Contributes to Adenovirus Binding?
• Ad11 ka = 1.18 x 106 M-1s-1, kb = 0.015 s-1
• Ad21 ka = 1.35 x 106 M-1s-1, kb = 0.383 s-1
Cupelli, et al. Structure of adenovirus type 21 knob in complex with CD46 reveals key differences. 2009
![Page 8: Electrostatic Interactions Between CD46(SCR1-2) and Ad11k-Ad21k](https://reader031.fdocuments.in/reader031/viewer/2022011722/58ee07801a28ab7d4a8b46d5/html5/thumbnails/8.jpg)
_ _ __ _ _+ + + _ _ _
_ _ _+ + +
+
++
+
Ad11Ad21 CD46
recognition
binding
Electrostatics Association Model
Gorham, et al. Electrostatic clustering and free energy calculations. 2011
![Page 9: Electrostatic Interactions Between CD46(SCR1-2) and Ad11k-Ad21k](https://reader031.fdocuments.in/reader031/viewer/2022011722/58ee07801a28ab7d4a8b46d5/html5/thumbnails/9.jpg)
Electrostatic Surface Map for CD46(SCR1-2)-Ad11k
Ad11k CD46(SCR1-2)
E196(A)
D284(A) R279(A)R280(A)
D300(E)
R266(E)
K119
E63
K29
R25
D27
Binding
E285(A)
Petteren, et al, “UCSF Chimera”, 2004
![Page 10: Electrostatic Interactions Between CD46(SCR1-2) and Ad11k-Ad21k](https://reader031.fdocuments.in/reader031/viewer/2022011722/58ee07801a28ab7d4a8b46d5/html5/thumbnails/10.jpg)
Electrostatic Surface Map for CD46(SCR1-2)-Ad21k
Ad21k
E148(B)
R195(B)
E208(B)R279(B) R247(B)
E299(C)
D179(C)
K119
R69 E63
K32 K29
D27
Binding
E302(C)
E292(B)
Petteren, et al, “UCSF Chimera”, 2004
CD46(SCR1-2)
![Page 11: Electrostatic Interactions Between CD46(SCR1-2) and Ad11k-Ad21k](https://reader031.fdocuments.in/reader031/viewer/2022011722/58ee07801a28ab7d4a8b46d5/html5/thumbnails/11.jpg)
Application of AESOP
• Performed Alanine scan mutations in both complexes to determine effects of thermodynamic stability on binding.
Ad11 or Ad21 CD46 Complex
DGAsolvation DGB
solvation DGABsolvation
DGref
DGsolu
ep = es = 20
ep = 20
es = 78.54
k = 0
k = 150
reference state
solvated state
Gorham, et al. Electrostatic clustering and free energy calculations. 2011
![Page 12: Electrostatic Interactions Between CD46(SCR1-2) and Ad11k-Ad21k](https://reader031.fdocuments.in/reader031/viewer/2022011722/58ee07801a28ab7d4a8b46d5/html5/thumbnails/12.jpg)
CD46(SCR1-2) Free Energy Plot (Ad11k)
3.5—5.0 Å
5.0—8.0 Å
“R: A language and environment for statistical computing”, 2011
![Page 13: Electrostatic Interactions Between CD46(SCR1-2) and Ad11k-Ad21k](https://reader031.fdocuments.in/reader031/viewer/2022011722/58ee07801a28ab7d4a8b46d5/html5/thumbnails/13.jpg)
CD46(SCR1-2) Free Energy Plot (Ad21k)
3.5—5.0 Å
5.0—8.0 Å
“R: A language and environment for statistical computing”, 2011
![Page 14: Electrostatic Interactions Between CD46(SCR1-2) and Ad11k-Ad21k](https://reader031.fdocuments.in/reader031/viewer/2022011722/58ee07801a28ab7d4a8b46d5/html5/thumbnails/14.jpg)
DGbind values for CD46(SCR1-2) mutants
CD46 ΔGbind (for Ad11 Complex) CD46 ΔGbind (for Ad21 Complex)
mutant kJ/mol mutant kJ/mol mutant kJ/mol mutant kJ/mol
WT 0 D27A (B) -6.20 WT 0 D27A (N) -1.61D47A (B) -0.03 D47A (N) 0.12
H43A (B) 2.30 D57A (B) -0.21 H43A (N) 0.05 D57A (N) -0.01H50A (B) -0.01 D58A (B) -0.13 H50A (N) 0.02 D58A (N) 0.11H90A (B) 0.01 D70A (B) -0.35 H90A (N) 0.00 D70A (N) -0.30
K15A (B) 0.92 E2A (B) 0.09 K15A (N) 1.25 E2A (N) -0.01K17A (B) -0.17 E3A (B) -0.05 K17A (N) 0.90 E3A (N) -0.41K29A (B) 1.93 E11A (B) -0.74 K29A (N) 0.34 E8A (N) -0.10K31A (B) 0.40 E21A (B) 0.10 K31A (N) 0.94 E11A (N) -0.61K32A (B) 0.69 E24A (B) 0.14 K32A (N) -1.59 E21A (N) -0.09K110A (B) 2.43 E63A (B) 6.39 K110A (N) 1.31 E24A (N) -0.58K119A (B) 4.58 E84A (B) 0.40 K119A (N) 5.04 E63A (N) 8.44K125A (B) 0.12 E8A (B) 0.06 K125A (N) 0.31 E84A (N) 0.24
E95A (B) 0.06 E95A (N) -0.12R25A (B) 4.06 E102A (B) -0.50 R25A (N) 1.16 E102A (N) -1.76R48A (B) 0.13 E103A (B) -0.08 R48A (N) -0.28 E103A (N) -0.39R62A (B) -0.29 E108A (B) -1.14 R62A (N) -0.02 E108A (N) -1.26R69A (B) 1.55 E124A (B) -0.54 R69A (N) 1.06 E124A (N) -0.78
![Page 15: Electrostatic Interactions Between CD46(SCR1-2) and Ad11k-Ad21k](https://reader031.fdocuments.in/reader031/viewer/2022011722/58ee07801a28ab7d4a8b46d5/html5/thumbnails/15.jpg)
Ad11k Free Energy Plot
3.5—5.0 Å
5.0—8.0 Å
“R: A language and environment for statistical computing”, 2011
![Page 16: Electrostatic Interactions Between CD46(SCR1-2) and Ad11k-Ad21k](https://reader031.fdocuments.in/reader031/viewer/2022011722/58ee07801a28ab7d4a8b46d5/html5/thumbnails/16.jpg)
DGbind values for Ad11k mutants
Ad11 ΔGbind values
mutant kJ/mol mutant kJ/mol mutant kJ/mol mutant kJ/mol
WT 0 R189A (A) 0.39 D129A (A) 0.08 E142A (A) 0.03R189A (E) -0.19 D129A (E) 0.03 E142A (E) 0.11
H188A (A) 0.04 R208A (A) 1.02 D155A (A) 1.00 E152A (A) 0.88H188A (E) -0.01 R208A (E) 0.10 D155A (E) 0.06 E152A (E) 0.12H218A (A) 0.00 R249A (A) 0.28 D200A (A) -0.27 E196A (A) 3.84H218A (E) 0.00 R249A (E) 0.03 D200A (E) -0.14 E196A (E) -0.04
R266A (A) 0.10 D246A (A) -0.41 E250A (A) -0.50K157A (A) -0.02 R266A (E) 4.28 D246A (E) -0.06 E250A (E) -0.04K157A (E) 0.06 R279A (A) 3.15 D265A (A) -0.08 E252A (A) -0.23K164A (A) -0.01 R279A (E) 0.07 D265A (E) 1.39 E252A (E) -0.01K164A (E) 0.06 R280A (A) 3.70 D272A (A) 0.51 E285A (A) -4.29K213A (A) -0.83 R280A (E) 0.09 D272A (E) 0.18 E285A (E) -0.19K213A (E) 0.00 R291A (A) -1.12 D284A (A) 3.74 E303A (A) -0.05K219A (A) -0.03 R291A (E) 0.06 D284A (E) -0.25 E303A (E) 0.96K219A (E) 0.01 R322A (A) 0.01 D300A (A) -0.13 E323A (A) -0.16K233A (A) 0.06 R322A (E) 0.03 D300A (E) 1.46 E323A (E) -0.09K233A (E) 0.14 D324A (A) 0.00K251A (A) 0.37 D324A (E) -0.06K251A (E) 0.00 D325A (A) 0.04
D325A (E) -0.05
![Page 17: Electrostatic Interactions Between CD46(SCR1-2) and Ad11k-Ad21k](https://reader031.fdocuments.in/reader031/viewer/2022011722/58ee07801a28ab7d4a8b46d5/html5/thumbnails/17.jpg)
Ad21k Free Energy Plot
3.5—5.0 Å
5.0—8.0 Å
“R: A language and environment for statistical computing”, 2011
![Page 18: Electrostatic Interactions Between CD46(SCR1-2) and Ad11k-Ad21k](https://reader031.fdocuments.in/reader031/viewer/2022011722/58ee07801a28ab7d4a8b46d5/html5/thumbnails/18.jpg)
DGbind values for Ad21k mutants
Ad21 ΔGbind values
mutant kJ/mol mutant kJ/mol mutant kJ/mol mutant kJ/mol
K139A (B) -0.08 WT 0 D151A (B) 1.06 E148A (B) 1.62K139A (C) 0.00 D151A (C) 0.51 E148A (C) 0.31K156A (B) -0.04 H254A (B) -0.03 D154A (B) 1.23 E208A (B) -0.99K156A (C) -0.38 H254A (C) 0.01 D154A (C) 0.50 E208A (C) 0.18K163A (B) -0.05 D179A (B) -0.02 E225A (B) 0.04K163A (C) -0.04 R195A (B) -5.30 D179A (C) 1.86 E225A (C) 0.03K188A (B) 0.05 R195A (C) -0.22 D199A (B) -0.11 E250A (B) 0.37K188A (C) -0.14 R247A (B) 0.91 D199A (C) 0.10 E250A (C) -0.05K212A (B) -1.90 R247A (C) -0.07 D207A (B) -0.45 E292A (B) 2.02K212A (C) -0.30 R265A (B) 0.2 D207A (C) 0.25 E292A (C) 0.16K216A (B) -0.08 R265A (C) 1.66 D248A (B) -0.01 E299A (B) -0.11K216A (C) -0.16 R279A (B) 3.29 D248A (C) -0.04 E299A (C) 1.22K218A (B) -0.03 R279A (C) -0.04 D264A (B) -0.20 E302A (B) -0.10K218A (C) -0.07 R319A (B) -0.07 D264A (C) -0.81 E302A (C) 2.47K231A (B) 0.08 R319A (C) -0.03 D321A (B) 0.04 E320A (B) -0.06K231A (C) 0.01 D321A (C) -0.01 E320A (C) -0.01K298A (B) 0.06 D322A (B) 0.04K298A (C) 0.03 D322A (C) 0.00
![Page 19: Electrostatic Interactions Between CD46(SCR1-2) and Ad11k-Ad21k](https://reader031.fdocuments.in/reader031/viewer/2022011722/58ee07801a28ab7d4a8b46d5/html5/thumbnails/19.jpg)
Intermolecular Coulombic InteractionsInteractions for CD46(SCR1-2)-Ad11k (Chain A) Interactions for CD46(SCR1-2)-Ad21k (Chain B)
CD46 res # atom Ad11 res # atom dist (Å) CD46 res # atom Ad21 res # atom dist (Å)
ARG 25 CZ GLU 285 CD 5 *GLU 11 CD GLU 148 CD 7.7
ARG 25 CZ ASP 284 CG 6.3 *ASP 27 CG GLU 208 CD 7.8
*ASP 27 CG GLU 285 CD 4.9 *LYS 29 NZ ARG 195 CZ 7.7
*ASP 27 CG ASP 284 CG 6.6 *LYS 29 NZ LYS 212 NZ 7.8
LYS 29 NZ GLU 196 CD 7.4 *LYS 32 NZ ARG 195 CZ 4.3GLU 63 CD ARG 280 CZ 4 LYS 32 NZ GLU 148 CD 7.1
GLU 63 CD ARG 279 CZ 7.7 LYS 32 NZ GLU 292 CD 7.9
GLU 63 CD ARG 247 CZ 4.5Interactions for CD46(SCR1-2)-Ad11k (Chain E) GLU 63 CD ARG 279 CZ 4
CD46 res # atom Ad11 res # atom dist (Å)
GLU 63 CD ARG 266 CZ 7.3 Interactions for CD46(SCR1-2)-Ad21k (Chain C)
LYS 119 NZ ASP 300 CG 6.1 CD46 res # atom Ad21 res # atom dist (Å)
ARG 69 CZ ASP 179 CG 6.1
LYS 119 NZ GLU 299 CD 4.6LYS 119 NZ GLU 302 CD 7.3
Bold-face = Interactions < 5 Å*Denotes unfavorable interactions
Bold-face = Interactions < 5 Å*Denotes unfavorable interactions
Ad11k favorable: 2 salt bridge, 5 weakAd11k unfavorable: 1 salt bridge, 1 weakAd11k contributing: 1 salt bridge, 4 weak
Ad21k favorable: 3 salt bridge, 4 weakAd21k unfavorable: 1 salt bridge, 4 weakAd21k contributing: 2 salt bridge
![Page 20: Electrostatic Interactions Between CD46(SCR1-2) and Ad11k-Ad21k](https://reader031.fdocuments.in/reader031/viewer/2022011722/58ee07801a28ab7d4a8b46d5/html5/thumbnails/20.jpg)
Intermolecular Hydrogen Bonds
Interactions for CD46(SCR1-2)-Ad11k (Chain A) Interactions for CD46(SCR1-2)-Ad21k (Chain B)
CD46 res # atom Ad11 res # atom dist (Å) CD46 res # atom AD21 res # atom dist (Å)
TYR 28 O ASN 283 ND2 3.7 CYS 30 N ILE 281 O 3.2
CYS 30 N ILE 282 O 3 TYR 36 N THR 280 O 2.7
CYS 30 SG ILE 282 O 3.4 THR 64 OG1 THR 245 O 2.6
TYR 36 N ALA 281 O 2.9 SER 112 O ARG 247 NH1 3.3
TYR 36 O ASN 245 ND2 3.3
THR 42 N ASP 284 OD2 2.8 Interactions for CD46(SCR1-2)-Ad21k (Chain C)
THR 42 OG1 ASP 284 N 3.1 CD46 res # atom AD21 res # atom dist (Å)
HIS 43 ND1 ASP 284 OD2 2.8 ARG 69 O ASN 304 ND2 3.5
SER 112 OG GLU 196 OE2 3.1 TRP 116 N TYR 263 O 3.2
LYS 119 NZ SER 300 O 3
Interactions for CD46(SCR1-2)-Ad11k (Chain E) PRO 120 O SER 303 OG 3.3
CD46 res # atom Ad11 res # atom dist (Å)
THR 64 O ARG 266 NH1 2.9
THR 64 O ARG 266 NH2 3.5
ALA 114 O ARG 266 NH1 2.8
Red = Negatively ChargedBlue = Positively Charged
Ad11k H-bonds: 12SASA: 641 Å
Red = Negatively ChargedBlue = Positively Charged
Ad21k H-bonds: 8SASA: 768 Å
![Page 21: Electrostatic Interactions Between CD46(SCR1-2) and Ad11k-Ad21k](https://reader031.fdocuments.in/reader031/viewer/2022011722/58ee07801a28ab7d4a8b46d5/html5/thumbnails/21.jpg)
Questions?