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.

Calibration of force‐field dependency in free energy landscapes of peptide conformations by quantum chemical calculations

“…The importance of the last complex modeling increases for structure‐based drug design, by overcoming the problem of induced local folding and polymorphism of ligand conformers. For those purposes, enhanced conformational sampling provides a quite powerful tool to derive the free energy landscapes and to predict the stable conformations in the sense of free energy 3–5. In addition, for short peptide fragments, it is now possible to reveal the entire conformational ensembles, which agree fairly well with experiments 6–8…”

A Modular Perspective of Protein Structures: Application to Fragment Based Loop Modeling

“…Active and binding site residues are more likely to be found in loop regions (31). Text book examples of functionally important loops include antibody complementary determining regions (32), ligand binding sites (ATP (33), calcium binding sites (34), NAD (P) (35)), DNA binding (36) or enzyme active sites (e.g. Ser-Thr kinases (37) or serine proteases (38)).…”

Computer-aided antibody design

“…For that purpose, Shirai et al (1998) and Kim et al (1999) performed the multicanonical molecular dynamics simulations (Nakajima et al , 1997; Higo et al , 2012) to probe the free energy landscapes, and they obtained the stable structural ensembles of the CDR-H3 loops at 300 K, which were found to include the corresponding crystal structures. In addition, characterizing the free energy landscapes should aid in predicting structural changes of CDR-H3 upon antigen binding based on the ‘population shift’ principle that suggests that bound conformations should be relatively close in free energy to the unbound state (Watanabe et al , 2006; Okazaki and Takada, 2008).…”