The indistinguishability of epitopes from protein surface is explained by the distinct binding preferences of each of the six antigen-binding loops

Kunik, Vered; Ofran, Yishai

doi:10.1093/protein/gzt027

Cited by 88 publications

(102 citation statements)

References 67 publications

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“…39 As shown above, CDRH2 is responsible the largest share of salt-bridges (39.66%). CDRH3 is the main source for H-bonds (30.14%) and all heavy chain CDRs take similar parts of the cation-pi interactions (20.57%, 22.7% and 26.24% of cation-pi interactions from CDRH3, CDRH1 and CDRH2, respectively).…”

Section: Data Sets Of Natural and Synthetic Absmentioning

confidence: 83%

“…[28][29][30] However, the relative importance of CDRH3 compared to other CDRs has been recently revisited in numerous studies. Large scale analyses 39,46 of Abs have assessed the role of CDRH3. It has been demonstrated that CDRH2 may be as important as CDRH3 46 in its contribution to the binding free energy of the Ab-Ag complex.…”

Section: Discussionmentioning

confidence: 99%

“…In another study, CDRH3 was found to be responsible for 30.6% of the energetically important Ag-binding residues. 39 That is, most of the energetically important Ag-binding residues come from other CDRs. This has been shown also for specific examples like the interaction between HyHEL-10 and lysozyme, in which CDRH2 and CDRL1 display a dominant role, while CDRH3 shows very low binding contribution.…”

Section: Discussionmentioning

confidence: 99%

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Understanding differences between synthetic and natural antibodies can help improve antibody engineering

Burkovitz

Ofran

2015

mAbs

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Synthetic libraries are a major source of human-like antibody (Ab) drug leads. To assess the similarity between natural Abs and the products of these libraries, we compared large sets of natural and synthetic Abs using "CDRs Analyzer," a tool we introduce for structural analysis of Ab-antigen (Ag) interactions. Natural Abs, we found, recognize their Ags by combining multiple complementarity-determining regions (CDRs) to create an integrated interface. Synthetic Abs, however, rely dominantly, sometimes even exclusively on CDRH3. The increased contribution of CDRH3 to Ag binding in synthetic Abs comes with a substantial decrease in the involvement of CDRH2 and CDRH1. Furthermore, in natural Abs CDRs specialize in specific types of non-covalent interactions with the Ag. CDRH1 accounts for a significant portion of the cation-pi interactions; CDRH2 is the major source of salt-bridges and CDRH3 accounts for most hydrogen bonds. In synthetic Abs this specialization is lost, and CDRH3 becomes the main sources of all types of contacts. The reliance of synthetic Abs on CDRH3 reduces the complexity of their interaction with the Ag: More Ag residues contact only one CDR and fewer contact 3 CDRs or more. We suggest that the focus of engineering attempts on CDRH3 results in libraries enriched with variants that are not naturallike. This may affect not only Ag binding, but also Ab expression, stability and selectivity. Our findings can help guide library design, creating libraries that can bind more epitopes and Abs that better mimic the natural antigenic interactions.

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Section: Data Sets Of Natural and Synthetic Absmentioning

confidence: 83%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

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Understanding differences between synthetic and natural antibodies can help improve antibody engineering

Burkovitz

Ofran

2015

mAbs

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“…1,2 The contribution of each of the six CDR loops to antigen recognition is different from each other, and even within a single CDR loop, each residue position plays a different role in antigen binding. 3,4 It is necessary, therefore, to characterize the sequence and structural properties of each position in a CDR loop for estimating the utilization of each position in antigen binding and for understanding antigen recognition in more detail. As mentioned above, the H3 loop is the main contributor to antigen recognition among the six CDR loops, because of its sequence diversity and location favorable to antigen binding.…”

Section: Introductionmentioning

confidence: 99%

The diversity of H3 loops determines the antigen‐binding tendencies of antibody CDR loops

Tsuchiya

Mizuguchi

2016

Protein Science

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Of the complementarity-determining regions (CDRs) of antibodies, H3 loops, with varying amino acid sequences and loop lengths, adopt particularly diverse loop conformations. The diversity of H3 conformations produces an array of antigen recognition patterns involving all the CDRs, in which the residue positions actually in contact with the antigen vary considerably. Therefore, for a deeper understanding of antigen recognition, it is necessary to relate the sequence and structural properties of each residue position in each CDR loop to its ability to bind antigens. In this study, we proposed a new method for characterizing the structural features of the CDR loops and obtained the antigen-binding ability of each residue position in each CDR loop. This analysis led to a simple set of rules for identifying probable antigen-binding residues. We also found that the diversity of H3 loop lengths and conformations affects the antigen-binding tendencies of all the CDR loops.

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“…It has been well accepted that the solvent accessible and protruding surface regions are more likely to be conformational epitopes (20)(21)(22)(23) and that the epitopes encompass substantially more loop residues than α-helix and β-strand residues (23,24). By contrast, the conclusions from various studies on the amino acid composition of conformational epitopes are not consistent (6), in large part due to the fact that the epitope amino acid composition is not particularly distinguishable from the nonantigenic solvent accessible surface area (6,7,22,23,25). The contradiction has been discussed recently (25), indicating that the physicochemical complementarity between the paratopes and the epitopes are strikingly incomparable, with overwhelmingly emphasized tyrosyl side chains in all CDR loops (25).…”

mentioning

confidence: 99%

Origins of specificity and affinity in antibody–protein interactions

Peng

Lee

Jian

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

178

283

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Natural antibodies are frequently elicited to recognize diverse protein surfaces, where the sequence features of the epitopes are frequently indistinguishable from those of nonepitope protein surfaces. It is not clearly understood how the paratopes are able to recognize sequence-wise featureless epitopes and how a natural antibody repertoire with limited variants can recognize seemingly unlimited protein antigens foreign to the host immune system. In this work, computational methods were used to predict the functional paratopes with the 3D antibody variable domain structure as input. The predicted functional paratopes were reasonably validated by the hot spot residues known from experimental alanine scanning measurements. The functional paratope (hot spot) predictions on a set of 111 antibody-antigen complex structures indicate that aromatic, mostly tyrosyl, side chains constitute the major part of the predicted functional paratopes, with short-chain hydrophilic residues forming the minor portion of the predicted functional paratopes. These aromatic side chains interact mostly with the epitope main chain atoms and side-chain carbons. The functional paratopes are surrounded by favorable polar atomistic contacts in the structural paratope-epitope interfaces; more that 80% these polar contacts are electrostatically favorable and about 40% of these polar contacts form direct hydrogen bonds across the interfaces. These results indicate that a limited repertoire of antibodies bearing paratopes with diverse structural contours enriched with aromatic side chains among short-chain hydrophilic residues can recognize all sorts of protein surfaces, because the determinants for antibody recognition are common physicochemical features ubiquitously distributed over all protein surfaces.protein antigenic site | interface hot spot | paratope prediction | epitope prediction | functional epitope I t is incompletely understood as to how functional antibodies can almost always be elicited against unlimited possibilities of protein antigens from a limited repertoire of antibodies. Antibodies provide protection against foreign protein antigens by recognizing the antigen proteins with exquisite specificity and remarkable affinity, but the principles underlying the antibody affinity and specificity remain elusive. Consequently, current antibody discoveries are by and large limited by the uncontrollable animal immune systems (1) or by the recombinant antibody libraries with relatively infinitesimal coverage of the vast combinatorial sequence space in antibody-antigen interaction interfaces (2). In developing the efficacy of a therapeutic antibody, optimizing the affinity and specificity of the antibody-antigen interaction mostly relies on selecting and screening from a large pool of random candidates. As antibodies are becoming the most prominent class of protein therapeutics (3), a better understanding of the principles governing antibody affinity and specificity will facilitate in understanding humoral immunity and in developing novel ...

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The indistinguishability of epitopes from protein surface is explained by the distinct binding preferences of each of the six antigen-binding loops

Cited by 88 publications

References 67 publications

Understanding differences between synthetic and natural antibodies can help improve antibody engineering

Understanding differences between synthetic and natural antibodies can help improve antibody engineering

The diversity of H3 loops determines the antigen‐binding tendencies of antibody CDR loops

Origins of specificity and affinity in antibody–protein interactions

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