TY - JOUR
T1 - Structural characterization of a protein a mimetic peptide dendrimer bound to human IgG
AU - Moiani, D.
AU - Salvalaglio, M.
AU - Cavallotti, C.
AU - Bujacz, A.
AU - Redzynia, I.
AU - Bujacz, G.
AU - Dinon, F.
AU - Pengo, P.
AU - Fassina, G.
PY - 2009/12/17
Y1 - 2009/12/17
N2 - Understanding the chemical physical properties of protein binding sites is at the basis of the rational design of protein ligands. The hinge region of the Fc fragment of immunoglobulin G is an important and well characterized protein binding site, known to interact with several natural proteins and synthetic ligands. Here, we report structural evidence that a Staphylococcus aureus Protein A mimetic peptide dendrimer, deduced by a combinatorial approach, binds close to the Cγ2/Cγ3 interface of the constant fragment of a human IgG1 molecule, partially hindering the Protein A binding site. The X-ray analysis evidenced a primary binding site located between a terminal Arg residue of the ligand peptidic arm and a hydrophobic protein site consisting of Val308, Leu309, and His310. A molecular dynamic analysis of the model derived from the X-ray structure showed that in water at room temperature the complex is further stabilized by the formation of at least one more contact between a terminal Arg residue of the second arm of the peptide and the carboxylic group of a protein amino acid, such as Glu318, Asp312, or Asp280. It appears thus that stability of the Fc-dendrimer complex is determined by the synergetic formation of multiple bonds of different nature between the dendrimer arms and the protein accessible sites. The electrostatic and van der Waals energies of the complex were monitored during the MD simulations and confirmed the energetic stability of the two interactions.
AB - Understanding the chemical physical properties of protein binding sites is at the basis of the rational design of protein ligands. The hinge region of the Fc fragment of immunoglobulin G is an important and well characterized protein binding site, known to interact with several natural proteins and synthetic ligands. Here, we report structural evidence that a Staphylococcus aureus Protein A mimetic peptide dendrimer, deduced by a combinatorial approach, binds close to the Cγ2/Cγ3 interface of the constant fragment of a human IgG1 molecule, partially hindering the Protein A binding site. The X-ray analysis evidenced a primary binding site located between a terminal Arg residue of the ligand peptidic arm and a hydrophobic protein site consisting of Val308, Leu309, and His310. A molecular dynamic analysis of the model derived from the X-ray structure showed that in water at room temperature the complex is further stabilized by the formation of at least one more contact between a terminal Arg residue of the second arm of the peptide and the carboxylic group of a protein amino acid, such as Glu318, Asp312, or Asp280. It appears thus that stability of the Fc-dendrimer complex is determined by the synergetic formation of multiple bonds of different nature between the dendrimer arms and the protein accessible sites. The electrostatic and van der Waals energies of the complex were monitored during the MD simulations and confirmed the energetic stability of the two interactions.
UR - http://www.scopus.com/inward/record.url?scp=73449120385&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=73449120385&partnerID=8YFLogxK
U2 - 10.1021/jp909405b
DO - 10.1021/jp909405b
M3 - Article
C2 - 19924842
AN - SCOPUS:73449120385
SN - 1520-6106
VL - 113
SP - 16268
EP - 16275
JO - Journal of Physical Chemistry B
JF - Journal of Physical Chemistry B
IS - 50
ER -