Stacking and energetic contribution of aromatic islands at the binding interface of antibody proteins

Immunome Research, Sep 2010

Background The enrichment and importance of some aromatic residues, such as Tyr and Trp, have been widely noticed at the binding interfaces of antibodies from many experimental and statistical results, some of which were even identified as “hot spots” contributing significantly greater to the binding affinity than other amino acids. However, how these aromatic residues influence the immune binding still deserves further investigation. A large-scale examination was done regarding the local spatial environment around the interfacial Tyr or Trp residues. Energetic contribution of these Tyr and Trp residues to the binding affinity was then studied regarding 82 representative antibody interfaces covering 509 immune complexes from the PDB database and IMGT/3Dstructure-DB. Results The connectivity analysis of interfacial residues showed that Tyr and Trp tended to cluster into the spatial Aromatic Islands (AI) rather than being distributed randomly at the antibody interfaces. Out of 82 antibody-antigen complexes, 72% (59) interfaces were found to contain AI with more than 3 aromatic residues. The statistical test against an empirical distribution indicated that the existence of AI was significant in about 60% representative antibody interfaces. Secondly, the loss of solvent accessible surface area (SASA) for side chains of aromatic residues between actually crowded state and independent state was nicely correlated with the AI size increasing in a linearly positive way which indicated that the aromatic side chains in AI tended to take a compact and ordered stacking conformation at the interfaces. Interestingly, the SASA loss of AI was also correlated roughly with the averaged gap of binding free energy between the theoretical and experimental data for immune complexes. Conclusions The results of our study revealed the wide existence and statistical significance of “Aromatic Island” (AI) composed of the spatially clustered Tyr and Trp residues at the antibody interfaces. The regular arrangement and stacking of aromatic side chains in AI could probably produce extra cooperative effects to the binding affinity which was firstly observed through the large-scale data analysis. The finding in this work not only provides insights into the functional role of aromatic residues in the antibody-antigen interaction, but also may facilitate the antibody engineering and potential clinical applications.

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Stacking and energetic contribution of aromatic islands at the binding interface of antibody proteins

Wu et al. Immunome Research Stacking and energetic contribution of aromatic islands at the binding interface of antibody proteins Di Wu 0 2 Jing Sun 0 2 Tianlei Xu 0 2 Shuning Wang 2 Guoqing Li 2 Yixue Li 1 2 Zhiwei Cao 0 2 0 Department of Biomedical Engineering, College Life Science and Technology, Tongji University , Shanghai, 200092 , China 1 Bioinformatics Center, Key Lab of Systems Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences , Shanghai 200031 , China 2 Shanghai Center for Bioinformation Technology , Qinzhou Rd 100, Building 1, 12F, Shanghai, 200235 , China Background: The enrichment and importance of some aromatic residues, such as Tyr and Trp, have been widely noticed at the binding interfaces of antibodies from many experimental and statistical results, some of which were even identified as “hot spots” contributing significantly greater to the binding affinity than other amino acids. However, how these aromatic residues influence the immune binding still deserves further investigation. A largescale examination was done regarding the local spatial environment around the interfacial Tyr or Trp residues. Energetic contribution of these Tyr and Trp residues to the binding affinity was then studied regarding 82 representative antibody interfaces covering 509 immune complexes from the PDB database and IMGT/3DstructureDB. Results: The connectivity analysis of interfacial residues showed that Tyr and Trp tended to cluster into the spatial Aromatic Islands (AI) rather than being distributed randomly at the antibody interfaces. Out of 82 antibody-antigen complexes, 72% (59) interfaces were found to contain AI with more than 3 aromatic residues. The statistical test against an empirical distribution indicated that the existence of AI was significant in about 60% representative antibody interfaces. Secondly, the loss of solvent accessible surface area (SASA) for side chains of aromatic residues between actually crowded state and independent state was nicely correlated with the AI size increasing in a linearly positive way which indicated that the aromatic side chains in AI tended to take a compact and ordered stacking conformation at the interfaces. Interestingly, the SASA loss of AI was also correlated roughly with the averaged gap of binding free energy between the theoretical and experimental data for immune complexes. Conclusions: The results of our study revealed the wide existence and statistical significance of “Aromatic Island” (AI) composed of the spatially clustered Tyr and Trp residues at the antibody interfaces. The regular arrangement and stacking of aromatic side chains in AI could probably produce extra cooperative effects to the binding affinity which was firstly observed through the large-scale data analysis. The finding in this work not only provides insights into the functional role of aromatic residues in the antibody-antigen interaction, but also may facilitate the antibody engineering and potential clinical applications. - From Asia Pacific Bioinformatics Network (APBioNet) Ninth International Conference on Bioinformatics (InCoB2010) Tokyo, Japan. 26-28 September 2010 Background It is well known that protein-protein interactions are fundamental to most of biological processes, including signal transduction, gene translation or transcription, enzyme activation or inhibition, and immune recognition. Contrast to the interaction between other normal protein-protein complexes, the binding between antibody and antigen is highly specific and stable [ 1 ]. Previous studies have revealed that this specificity is dominantly determined by the contacting interface which is mainly composed of the variable domains of antibody [ 2-6 ]. It has been reported that with only 5% sequence change in the variable domains, antibodies can recognize specifically and bind tightly to 1010 different antigens [ 7 ]. It is always interesting to study how antibody can recognize so large variety of antigens with so little change in sequence and thus deserve further investigation. Characteristics of the binding interfaces of antibodies such as the size, shape, chemical, physical or structural complementation have been analyzed from different perspectives for a deeper understanding to antibody-antigen interactions [ 8-10 ]. Although the hydrophobic effect was considered as the major driving force for the general protein binding, the study of Tsai and co-workers indicated that hydrophobic amino acids were not the dominant part and a higher proportion of charged and polar residues could be found at the binding interfaces [ 11 ]. Subsequent comparison between the interfaces of six antibody-antigen complexes and other protein-protein complexes reported that the residues composing the interface of antibody-antigen complexes were more polar, protruding and accessible [ 12 ]. Currently, more and more results suggest that there are significant differences between the interfac (...truncated)


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Di Wu, Jing Sun, Tianlei Xu, Shuning Wang, Guoqing Li, Yixue Li, Zhiwei Cao. Stacking and energetic contribution of aromatic islands at the binding interface of antibody proteins, Immunome Research, 2010, pp. S1, Volume 6, Issue S1, DOI: 10.1186/1745-7580-6-S1-S1