title: Enhanced conformational diversity search of CDR-H3 in antibodies: role of the first CDR-H3 residue.
abstract: Through a conformation search by a simulation calculation, the relationships between the amino acid sequences and the conformations of the third complementarity-determining region of the antibody heavy chain (CDR-H3) were investigated to characterize the large conformational varieties of antibodies. Here, we focused on the structural role of the first CDR-H3 residue, and we selected two antibodies, 28B4 and PLG, whose CDR-H3 conformations are significantly different, having Trp and Gly at the first position, respectively. Multicanonical molecular dynamics simulations, with the advantage of enhanced sampling efficiency, were performed for the CDR-H3 fragments of 28B4 and PLG, and a modified CDR-H3 model of 28B4, where the first Trp residue was substituted with Gly. When the first CDR-H3 residue is Trp, almost all of the observed CDR-H3 loops were bent at the first residue. In contrast, when the first residue is Gly, large varieties of loop conformations were observed. The structural role of this Gly residue is discussed from the perspective of the other antibody structures in the database. When the surrounding residues were included in the calculations, CDR-H3 loop structures similar to those in the crystal structures were reproduced as the major conformations for both the 28B4 and PLG antibodies.
authors.affiliation: Department of Bioinformatics, Biomolecular Engineering Research Institute, Osaka, Japan.
authors.forename: S T
authors.initials: ST
authors.lastname: Kim
authors.forename: H
authors.initials: H
authors.lastname: Shirai
authors.forename: N
authors.initials: N
authors.lastname: Nakajima
authors.forename: J
authors.initials: J
authors.lastname: Higo
authors.forename: H
authors.initials: H
authors.lastname: Nakamura
mesh_terms: D000465:Algorithms; D000595:Amino Acid Sequence; D019943:Amino Acid Substitution; D000916:Antibody Diversity; D018360:Crystallography, X-Ray; D005998:Glycine / Q000737:chemistry; D006801:Humans; D007143:Immunoglobulin Heavy Chains / Q000737:chemistry* / Q000235:genetics; D007147:Immunoglobulin Light Chains / Q000737:chemistry / Q000235:genetics; D007135:Immunoglobulin Variable Region / Q000737:chemistry* / Q000235:genetics; D008958:Models, Molecular; D008969:Molecular Sequence Data; D010446:Peptide Fragments / Q000737:chemistry / Q000235:genetics / Q000276:immunology; D011487:Protein Conformation; D017386:Sequence Homology, Amino Acid; D013816:Thermodynamics
chemical_list: D007143:Immunoglobulin Heavy Chains; D007147:Immunoglobulin Light Chains; D007135:Immunoglobulin Variable Region; D010446:Peptide Fragments; D005998:Glycine