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Electrostatic Interactions between Complement Regulator CD46(SCR1-2) and Adenovirus Ad11/Ad21 Fiber Protein Knob.

Chen CZ, Gorham RD, Gaieb Z, Morikis D - Mol Biol Int (2015)

Bottom Line: Our results delineate specific interfacial electrostatic interactions that are critical for association in both CD46(SCR1-2)-Ad11k and CD46(SCR1-2)-Ad21k.These results will serve as a predictive tool in the selection of mutants with desired binding affinity in experimental mutagenesis studies.This study will also serve as a foundation for the design of inhibitors to treat adenovirus infections.

View Article: PubMed Central - PubMed

Affiliation: Department of Bioengineering, University of California, Riverside, CA 92521, USA.

ABSTRACT
Adenoviruses bind to a variety of human cells to cause infection. Both the B2 adenovirus 11 and B1 adenovirus 21 use protein knobs to bind to complement regulator CD46(SCR1-2) in order to gain entry into host cells. In each complex, the two proteins are highly negatively charged but bind to each other at an interface with oppositely charged surface patches. We computationally generated single-alanine mutants of charged residues in the complexes CD46(SCR1-2)-Ad11k and CD46(SCR1-2)-Ad21k. We used electrostatic clustering and Poisson-Boltzmann free energy calculations to propose a hypothesis on the role of electrostatics in association. Our results delineate specific interfacial electrostatic interactions that are critical for association in both CD46(SCR1-2)-Ad11k and CD46(SCR1-2)-Ad21k. These results will serve as a predictive tool in the selection of mutants with desired binding affinity in experimental mutagenesis studies. This study will also serve as a foundation for the design of inhibitors to treat adenovirus infections.

No MeSH data available.


Related in: MedlinePlus

Maps of electrostatic free energy of binding for CD46(SCR1-2)-Ad21k at the binding site (a) and at the surface opposite to the binding site (b). Presentation and notation is as in Figure 5.
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fig6: Maps of electrostatic free energy of binding for CD46(SCR1-2)-Ad21k at the binding site (a) and at the surface opposite to the binding site (b). Presentation and notation is as in Figure 5.

Mentions: Through a systematic alanine scan of charged residues, we determined the contribution of each charged amino acid to the electrostatic component of the binding free energy in both complexes. We calculated electrostatic free energies of binding for the two families of mutants and parent proteins, as described in Section 2.4. Figure 4 shows graphs of differences between electrostatic free energies of binding (1) for CD46(SCR1-2) from its complexes with the Ad11k (Figure 4(a)) and Ad21k (Figure 4(b)), respectively. Supplementary Figures S2 and S3 show similar graphs for Ad11k and Ad21k. Positive ΔGbinding values indicate that the complex is thermodynamically less stable than the parent protein complex, whereas negative ΔGbinding values indicate a more stable complex than the parent complex. Thus, a positive ΔGbinding sign indicates a loss of binding, whereas a negative ΔGbinding sign indicates a gain of binding upon mutation. The free energy maps of Figures 5 and 6 show the location of individual residues that have experienced significant loss or gain of binding (See Supplementary Tables 1–3 for ΔGbinding values). In both complexes, the majority of mutations resulted in a loss of binding. Mutated residues that contribute to more than 2.5 kJ/mol in the free energy differences are considered to be more influential for binding, and they are marked in Figure 4 (the chosen 2.5 kJ/mol value corresponds to the thermal energy at room temperature).


Electrostatic Interactions between Complement Regulator CD46(SCR1-2) and Adenovirus Ad11/Ad21 Fiber Protein Knob.

Chen CZ, Gorham RD, Gaieb Z, Morikis D - Mol Biol Int (2015)

Maps of electrostatic free energy of binding for CD46(SCR1-2)-Ad21k at the binding site (a) and at the surface opposite to the binding site (b). Presentation and notation is as in Figure 5.
© Copyright Policy - open-access
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC4556874&req=5

fig6: Maps of electrostatic free energy of binding for CD46(SCR1-2)-Ad21k at the binding site (a) and at the surface opposite to the binding site (b). Presentation and notation is as in Figure 5.
Mentions: Through a systematic alanine scan of charged residues, we determined the contribution of each charged amino acid to the electrostatic component of the binding free energy in both complexes. We calculated electrostatic free energies of binding for the two families of mutants and parent proteins, as described in Section 2.4. Figure 4 shows graphs of differences between electrostatic free energies of binding (1) for CD46(SCR1-2) from its complexes with the Ad11k (Figure 4(a)) and Ad21k (Figure 4(b)), respectively. Supplementary Figures S2 and S3 show similar graphs for Ad11k and Ad21k. Positive ΔGbinding values indicate that the complex is thermodynamically less stable than the parent protein complex, whereas negative ΔGbinding values indicate a more stable complex than the parent complex. Thus, a positive ΔGbinding sign indicates a loss of binding, whereas a negative ΔGbinding sign indicates a gain of binding upon mutation. The free energy maps of Figures 5 and 6 show the location of individual residues that have experienced significant loss or gain of binding (See Supplementary Tables 1–3 for ΔGbinding values). In both complexes, the majority of mutations resulted in a loss of binding. Mutated residues that contribute to more than 2.5 kJ/mol in the free energy differences are considered to be more influential for binding, and they are marked in Figure 4 (the chosen 2.5 kJ/mol value corresponds to the thermal energy at room temperature).

Bottom Line: Our results delineate specific interfacial electrostatic interactions that are critical for association in both CD46(SCR1-2)-Ad11k and CD46(SCR1-2)-Ad21k.These results will serve as a predictive tool in the selection of mutants with desired binding affinity in experimental mutagenesis studies.This study will also serve as a foundation for the design of inhibitors to treat adenovirus infections.

View Article: PubMed Central - PubMed

Affiliation: Department of Bioengineering, University of California, Riverside, CA 92521, USA.

ABSTRACT
Adenoviruses bind to a variety of human cells to cause infection. Both the B2 adenovirus 11 and B1 adenovirus 21 use protein knobs to bind to complement regulator CD46(SCR1-2) in order to gain entry into host cells. In each complex, the two proteins are highly negatively charged but bind to each other at an interface with oppositely charged surface patches. We computationally generated single-alanine mutants of charged residues in the complexes CD46(SCR1-2)-Ad11k and CD46(SCR1-2)-Ad21k. We used electrostatic clustering and Poisson-Boltzmann free energy calculations to propose a hypothesis on the role of electrostatics in association. Our results delineate specific interfacial electrostatic interactions that are critical for association in both CD46(SCR1-2)-Ad11k and CD46(SCR1-2)-Ad21k. These results will serve as a predictive tool in the selection of mutants with desired binding affinity in experimental mutagenesis studies. This study will also serve as a foundation for the design of inhibitors to treat adenovirus infections.

No MeSH data available.


Related in: MedlinePlus