Molecular dynamics, free energy, and SPR analyses of the interactions between the SH2 domain of Grb2 and ErbB phosphotyrosyl peptides.
We studied the interactions between the SH2 domain of growth factor receptor binding protein 2 (Grb2) and ErbB receptor-derived phosphotyrosyl peptides using molecular dynamics, free energy calculations, and surface plasmon resonance (SPR) analysis. Binding free energies for nine phosphotyrosyl peptides were calculated using the MM-PBSA continuum solvent method, and excellent qualitative agreement with the SPR experimental data, with a correlation coefficient of 0.92, was obtained. Consistent with previous experimental findings, phosphotyrosyl peptides with the consensus sequence pYXNX showed favorable binding affinity for the Grb2. Unexpectedly, phosphotyrosyl peptides with the consensus sequence pYQQD, which had not shown any specific binding affinity for the Grb2 in earlier studies, also showed favorable binding affinity for the Grb2 in our experimental and computational analyses. Component analysis of the calculated binding free energies revealed that van der Waals interaction between the Grb2 and the phosphotyrosyl peptide was the dominant factor for specificity and binding affinity. These results indicate that current methods of estimating binding free energies are efficient for obtaining important information about protein-protein interactions, which are essential for the transmission of signals in cellular signaling pathways.
Bioinformatics Group, RIKEN Genomic Sciences Center, Yokohama, Kanagawa, Japan. suenaga@gsc.riken.go.jp
Atsushi
A
Suenaga
Mariko
M
Hatakeyama
Mio
M
Ichikawa
Xiaomei
X
Yu
Noriyuki
N
Futatsugi
Tetsu
T
Narumi
Kazuhiko
K
Fukui
Takaho
T
Terada
Makoto
M
Taiji
Mikako
M
Shirouzu
Shigeyuki
S
Yokoyama
Akihiko
A
Konagaya
D048868:Adaptor Proteins, Signal Transducing; D003198:Computer Simulation; D066246:ErbB Receptors / Q000737:chemistry / Q000378:metabolism*; D051380:GRB2 Adaptor Protein; D005982:Glutathione Transferase / Q000378:metabolism; D006801:Humans; D007700:Kinetics; D008024:Ligands; D010446:Peptide Fragments / Q000737:chemistry / Q000378:metabolism*; D019000:Phosphotyrosine; D011485:Protein Binding; D011487:Protein Conformation; D017510:Protein Folding; D011506:Proteins / Q000737:chemistry / Q000378:metabolism*; D066247:Receptor, ErbB-4; D011993:Recombinant Fusion Proteins / Q000302:isolation & purification / Q000378:metabolism; D013816:Thermodynamics; D014443:Tyrosine / Q000031:analogs & derivatives* / Q000737:chemistry / Q000378:metabolism; D018909:src Homology Domains
D048868:Adaptor Proteins, Signal Transducing; D051380:GRB2 Adaptor Protein; C495948:GRB2 protein, human; D008024:Ligands; D010446:Peptide Fragments; D011506:Proteins; D011993:Recombinant Fusion Proteins; D019000:Phosphotyrosine; D014443:Tyrosine; D005982:Glutathione Transferase; C587689:ERBB4 protein, human; D066246:ErbB Receptors; D066247:Receptor, ErbB-4