Binding Mechanism of CD47 with SIRPα Variants and Its Antibody: Elucidated by Molecular Dynamics Simulations
Abstract
:1. Introduction
2. Results
2.1. Static Structural Information Analysis
2.2. Structural Stability during Simulations
2.3. Characterization of Protein Druggable Sites
2.4. Dynamic Mechanism and Structural Change
2.5. Binging Free Energy Analysis
2.6. Energy Decomposition and Analysis of the Binding Hot Spots
2.7. Dynamical Structure Analysis
2.7.1. Hydrogen Bonds in the Complexes
2.7.2. Salt Bridges
2.7.3. Dynamical Residue Contacts
2.8. Dynamical Correlation Analysis of CD47 Proteins
3. Discussion
4. Materials and Methods
4.1. Structure Preparation
4.2. MD Simulations
4.3. Free Energy Calculations and Decomposition
4.4. Trajectory Analysis
4.5. Dynamical Residue Contacts Analysis
4.6. Correlation Analysis of Dynamical Motions
5. Conclusions
Supplementary Materials
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Conflicts of Interest
Sample Availability
References
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CD47 Residues | Partner Residues a |
---|---|
CD47-SIRPαv1: | |
Gln1, Leu2, Leu3, Lys6, Asn27, Glu29, Ala30, Gln31, Thr34, Glu35, Val36, Tyr37, Lys39, Asp46, Thr49, Glu97, Thr99, Glu100, Leu101, Thr102, Arg103, Glu104, Gly105, Glu106 | Ser29, Leu30, Ile31, Pro32, Val33, Gly34, Pro35, Ile36, Gln37, Tyr50, Asn51, Gln52, Lys53, Glu54, Leu66, Thr67, Lys68, Arg69, Phe74, Lys93, Lys96, Gly97, Ser98, Pro99, Asp100, Asp101 |
CD47-SIRPαv2: | |
Gln1, Leu2, Leu3, Lys6, Asn27, Glu29, Ala30,Gln31, Thr34, Glu35, Val36, Tyr37, Lys39, Lys41, Asp46, Thr49, Glu97, Thr99, Glu100, Leu101, Thr102, Arg103, Glu104, Gly105, Glu106 | Ser29, Leu30, Ile31, Pro32, Val33, Gly34, Pro35, Ile36, Gln37, Tyr50, Asn51, Gln52, Lys53, Glu54, His56, Ser66, Thr67, Lys68, Arg69, Glu70, Phe74, Lys93, Lys96, Gly97, Ser98, Pro99, Asp100 |
CD47-B6H12.2 b: | |
Met28, Glu29, Ala30, Gln31, Asn32, Thr34, Glu35, Val36, Tyr37, Lys39, Asp46, Asp51, Ala53, Leu54, Glu97, Thr99, Glu100, Leu101, Thr102, Arg103, Glu104 | Ser30LC, Asp31LC, Tyr32LC, Lys49LC, Phe50LC, Gln52LC, Gly91LC, His92LC, Gly93LC, Phe94LC, Arg96LC, Ser30HC, Gly31HC, Tyr32HC, Gly33HC, Trp47HC, Thr50HC, Ile51HC, Thr52HC, Ser53HC, Gly54HC, Gly55HC, Thr56HC, Tyr57HC, Tyr59HC, Ser99HC, Leu100HC, Ala101HC, Gly102HC, Asn103HC |
Contribution | CD47-SIRPαv1 | CD47-SIRPαv2 | CD47-B6H12.2 |
---|---|---|---|
ΔEele | −557.87 ± 72.76 | −522.69 ± 69.19 | −549.61 ± 29.91 |
ΔEvdw | −89.88 ± 6.72 | −86.09 ± 8.99 | −97.56 ± 6.01 |
ΔEgas b | −647.74 ± 73.77 | −608.78 ± 72.85 | −647.17 ± 29.57 |
ΔGsol-polar | 575.80 ± 68.36 | 540.53 ± 63.17 | 565.76 ± 26.28 |
ΔGsol-np | −14.54 ± 0.79 | −13.76 ± 1.35 | −13.99 ± 0.58 |
ΔGsol c | 561.27 ± 67.84 | 526.78 ± 62.13 | 551.77 ± 26.09 |
ΔHtot d | −86.48 ± 9.72 | −82.00 ± 13.26 | −95.40 ± 7.85 |
TΔS e | −53.75 ± 6.78 | −54.55 ± 5.78 | −51.76 ± 7.24 |
ΔGbind f | −32.73 | −27.45 | −43.64 |
Kd | 0.74 ± 0.07 μM | 0.64 ± 0.06 μM | 0.5 nM |
Acceptor Residues | Acceptor Atoms | Donor Residues | Donor Atoms | Fraction 1 b | Fraction 2 | Fraction 3 |
---|---|---|---|---|---|---|
CD47-SIRPαv1: | ||||||
SIRPα_Thr67 | O | CD47_Arg103 | NH1 | 88.39% | 84.93% | 91.16% |
CD47_Leu101 | O | SIRPα_Gly34 | N | 79.75% | 73.11% | 80.38% |
CD47_Glu35 | OE2 | SIRPα_Arg69 | NH2 | 49.75% | 49.16% | 52.81% |
CD47_Glu35 | OE1 | SIRPα_Arg69 | NH2 | 49.22% | 50.90% | 48.36% |
CD47_Glu35 | OE1 | SIRPα_Arg69 | NH1 | 34.85% | 45.86% | 43.36% |
CD47_Glu35 | OE2 | SIRPα_Arg69 | NH1 | 27.67% | 41.40% | 47.19% |
CD47-SIRPαv2: | ||||||
SIRPα_Thr67 | O | CD47_Arg103 | NH1 | 86.75% | 90.19% | 85.80% |
CD47_Leu101 | O | SIRPα_Gly34 | N | 85.18% | 83.24% | 83.27% |
CD47_Glu35 | OE1 | SIRPα_Arg69 | NH2 | 50.61% | 48.62% | 52.99% |
CD47_Glu35 | OE2 | SIRPα_Arg69 | NH2 | 51.46% | 52.00% | 47.72% |
CD47_Glu35 | OE2 | SIRPα_Arg69 | NH1 | 51.63% | 46.76% | 49.83% |
CD47_Glu100 | OE1 | SIRPα_Arg69 | NH1 | 49.31% | 45.71% | 41.79% |
CD47_Glu100 | OE2 | SIRPα_Arg69 | NH1 | 37.97% | 41.74% | 45.84% |
CD47_Glu35 | OE1 | SIRPα_Arg69 | NH1 | 39.36% | 44.43% | 41.80% |
CD47-B6H12.2: | ||||||
CD47_Thr99 | OG1 | LC_His92 | NE2 | 77.36% | 71.15% | 67.44% |
CD47_Glu100 | O | HC_Gly102 | N | 76.87% | 80.10% | 80.90% |
HC_Gly31 | O | CD47_Thr34 | OG1 | 70.27% | 63.52% | 68.58% |
CD47_Asp51 | OD2 | LC_Gln53 | NE2 | 62.09% | 53.64% | 36.49% |
CD47_Glu104 | OE1 | LC_Arg96 | NH1 | 55.32% | 53.87% | 41.68% |
CD47_Leu101 | O | LC_Arg96 | NE | 54.75% | 55.88% | 49.23% |
CD47_Glu35 | OE1 | HC_Ser53 | OG | 52.38% | 53.57% | 34.55% |
CD47_Glu35 | OE2 | HC_Ser53 | OG | 46.38% | 45.29% | 63.99% |
CD47_Glu97 | OE2 | LC_Tyr32 | OH | 50.82% | 41.96% | 48.33% |
CD47_Glu97 | OE1 | LC_Tyr32 | OH | 42.93% | 50.97% | 46.96% |
CD47_Glu104 | OE2 | LC_Arg96 | NH1 | 41.36% | 44.13% | 55.27% |
Negative Residues b | Positive Residues | Fraction 1 c | Fraction 2 | Fraction 3 |
---|---|---|---|---|
CD47-SIRPαv1: | ||||
CD47_Glu35 | SIRPαv1_Arg69 | 32.66% | 43.16% | 45.53% |
CD47_Glu97 | SIRPαv1_Lys96 | 18.49% | 32.07% | 74.37% |
CD47_Glu97 | SIRPαv1_Lys53 | 45.35% | 15.85% | 40.15% |
CD47_Asp51 | SIRPαv1_Arg95 | 36.37% | 35.15% | 42.20% |
CD47_Glu104 | SIRPαv1_Lys96 | 78.59% | 31.45% | 4.53% |
CD47_Glu104 | SIRPαv1_Lys53 | 4.59% | 24.19% | 48.76% |
CD47-SIRPαv2: | ||||
CD47_Glu35 | SIRPαv2_Arg69 | 50.01% | 49.77% | 52.45% |
CD47_Asp51 | SIRPαv2_Arg95 | 41.00% | 44.15% | 35.85% |
CD47_Glu97 | SIRPαv2_Lys96 | 17.95% | 59.08% | 36.13% |
CD47_Glu104 | SIRPαv2_Lys53 | 18.07% | 34.29% | 35.60% |
CD47_Glu106 | SIRPαv2_Lys53 | 27.74% | 20.61% | 38.96% |
CD47_Glu97 | SIRPαv2_Lys53 | 24.54% | 43.30% | 5.95% |
CD47-B6H12.2: | ||||
CD47_Asp51 | LC_Lys49 | 99.56% | 99.77% | 99.78% |
LC_Asp31 | CD47_Lys39 | 28.65% | 35.78% | 60.68% |
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Huang, K.; Liu, Y.; Wen, S.; Zhao, Y.; Ding, H.; Liu, H.; Kong, D.-X. Binding Mechanism of CD47 with SIRPα Variants and Its Antibody: Elucidated by Molecular Dynamics Simulations. Molecules 2023, 28, 4610. https://doi.org/10.3390/molecules28124610
Huang K, Liu Y, Wen S, Zhao Y, Ding H, Liu H, Kong D-X. Binding Mechanism of CD47 with SIRPα Variants and Its Antibody: Elucidated by Molecular Dynamics Simulations. Molecules. 2023; 28(12):4610. https://doi.org/10.3390/molecules28124610
Chicago/Turabian StyleHuang, Kaisheng, Yi Liu, Shuixiu Wen, Yuxin Zhao, Hanjing Ding, Hui Liu, and De-Xin Kong. 2023. "Binding Mechanism of CD47 with SIRPα Variants and Its Antibody: Elucidated by Molecular Dynamics Simulations" Molecules 28, no. 12: 4610. https://doi.org/10.3390/molecules28124610
APA StyleHuang, K., Liu, Y., Wen, S., Zhao, Y., Ding, H., Liu, H., & Kong, D. -X. (2023). Binding Mechanism of CD47 with SIRPα Variants and Its Antibody: Elucidated by Molecular Dynamics Simulations. Molecules, 28(12), 4610. https://doi.org/10.3390/molecules28124610