Antigen–antibody interface properties: Composition, residue interactions, and features of 53 non-redundant structures

Abstract

The structures of protein antigen–antibody (Ag–Ab) interfaces contain information about how Ab recognize Ag as well as how Ag are folded to present surfaces for Ag recognition. As such, the Ab surface holds information about Ag folding that resides with the Ab–Ag interface residues and how they interact. In order to gain insight into the nature of such interactions, a data set comprised of 53 non-redundant 3D structures of Ag–Ab complexes was analyzed. We assessed the physical and biochemical features of the Ag–Ab interfaces and the degree to which favored interactions exist between amino acid residues on the corresponding interface surfaces. Amino acid compositional analysis of the interfaces confirmed the dominance of TYR in the Ab paratope-containing surface (PCS), with almost two fold greater abundance than any other residue. Additionally TYR had a much higher than expected presence in the PCS compared to the surface of the whole antibody (defined as the occurrence propensity), along with aromatics PHE, TRP, and to a lesser degree HIS and ILE. In the Ag epitope-containing surface (ECS), there were slightly increased occurrence propensities of TRP and TYR relative to the whole Ag surface, implying an increased significance over the compositionally most abundant LYS>ASN>GLU>ASP>ARG. This examination encompasses a large, diverse set of unique Ag–Ab crystal structures that help explain the biological range and specificity of Ag–Ab interactions. This analysis may also provide a measure of the significance of individual amino acid residues in phage display analysis of Ag binding.

Unique motifs and hydrophobic interactions shape the binding of modified DNA ligands to protein targets

“…We have shown here that the hydrophobic functional groups of SOMAmers augment the contours of the binding surface and its physicochemical complexity beyond that which can be achieved with natural nucleic acids. This situation is similar to antibodies where relatively limited shape diversity of the canonical main-chain conformations in CDRs (39) is enhanced with amino acids that can sweep out large volumes of space, interspaced with smaller amino acids that allow such motions to take place (15,16). Indeed, CDR libraries composed of only two amino acids, tyrosine and serine, which are overrepresented in CDRs, have been used to derive specific antibodies with relatively high affinity (40).…”

“…For this purpose, we designed a library to allow us to probe the microenvironment of each of the positions by varying the size, polarity, disposition of H-bond donors and acceptors, linker length, and orientation of the 5-position substituents. In choosing the functional groups for this analysis, we aimed to include variations on a theme of the original modification (in this case, the benzyl group), amino acid side chains overrepresented in complementarity determining regions (CDRs) of antibodies (such as tryptophan and tyrosine) (15,16), and "privileged" fragments of small-molecule drugs (17). In a sense, we endeavored to combine elements of affinity maturation in antibodies and structure-activity relationship optimization in medicinal chemistry.…”

Identification of a Neutralizing Epitope within Antigenic Domain 5 of Glycoprotein B of Human Cytomegalovirus

“…Nevertheless, single residues have been identified as "hot spots" and as critical for antibody binding and function, since they contribute the majority of binding energy in the antibody-antigen interaction (48). Tyrosine residues have frequently been found in interaction "hot spots" (48,49). By analogy, similar neutralizing antibody escape mutants carrying a single amino acid exchange to render a virus resistant to antibodymediated neutralization have been described for other viral systems, such as HIV or influenza virus (50)(51)(52).…”

“…In the case of the AD-5-specific MAbs investigated in the current study, the space occupied by the defined critical residues covers around 560 Å 2 . Nevertheless, single residues have been identified as "hot spots" and as critical for antibody binding and function, since they contribute the majority of binding energy in the antibody-antigen interaction (48). Tyrosine residues have frequently been found in interaction "hot spots" (48,49).…”

MoFvAb: Modeling the Fv region of antibodies

“…The bulky aromatic sidechains of tryptophan and tyrosine residues often constitute important players in antibody-antigen binding motifs. [45][46][47] Therefore, the correct placement of these residues at key positions is crucial to obtain a precise antibody homology model. In this example, the tryptophan W197/H33 from the original template 1ngz_B (the CDR-H1 loop of 1ngz_B has 100% identity to the query sequence) is replaced by a tyrosine from a different structure, based on the neighborhood query 'WjHRDPXGKMWYY', matched by Y197/H33 with neighborhood string 'YjHRDPXNKFGYY' in template 1j05_H.…”