MoFvAb: Modeling the Fv region of antibodies

Abstract

Knowledge of the 3-dimensional structure of the antigen-binding region of antibodies enables numerous useful applications regarding the design and development of antibody-based drugs. We present a knowledge-based antibody structure prediction methodology that incorporates concepts that have arisen from an applied antibody engineering environment. The protocol exploits the rich and continuously growing supply of experimentally derived antibody structures available to predict CDR loop conformations and the packing of heavy and light chain quickly and without user intervention. The homology models are refined by a novel antibody-specific approach to adapt and rearrange sidechains based on their chemical environment. The method achieves very competitive all-atom root mean square deviation values in the order of 1.5 A on different evaluation datasets consisting of both known and previously unpublished antibody crystal structures.

ABodyBuilder: Automated antibody structure prediction with data–driven accuracy estimation

“…The template's light chain framework region had a backbone RMSD of 1.5Å. Furthermore, the target structure has an unusual tilt angle, as previously commented; 15 our chosen template had a high deviation in tilt angle with respect to the target structure. Both features could have affected the choice of the CDRL1 loop by FREAD.…”

“… 7,12-14 Alternatively, a fragment-based method can be used to assemble the VH and VL domains. 15 The VH–VL orientation 21 is then modeled after choosing the framework template. 22 In the third stage, the ‘canonical’ CDR loops (CDRH1, CDRH2, CDRL1, CDRL2, CDRL3) are modeled, followed by CDRH3.…”

Characterization of a re‐engineered, mesothelin‐targeted Pseudomonas exotoxin fusion protein for lung cancer therapy

“…Two other lines, T3M-10 and NCI-H292, were completely growth inhibited, while proliferation of NCI-H2052 and DV90 cells structures of SS1P and RG7787 as well as the 7 amino acid substitutions (red balls) within the catalytic domain III of PE that were introduced in RG7787 to silence all 6 known human B-cell epitopes. The mutated PE24 was modeled onto the crystal structure of PE (structure 1IKQ in the Research Collaboratory for Structural Bioinformatics protein data base), the linker with the furin cleavage site was modeled as linear peptide chain and energy minimized, and the Fab fragment was modeled onto fragments of different Fv structures and refined as described in Bujotzek et al, 2015. (B) The graph shows typical competition curves obtained using serum from an SS1P-treated patient with a neutralizing anti-drug antibody response. In this case the concentrations of RG7787 and SS1P at which binding to PE38 was inhibited by 50% (IC 50 ) were 7.7 nM and 0.005 nM, respectively.…”

DynaDom: structure-based prediction of T cell receptor inter-domain and T cell receptor-peptide-MHC (class I) association angles

“…This last comment is in agreement with recent observations about the dynamics of the TCRpMHC system and the influence of the TCR on the pMHC structure [ 44 , 47 ]. In addition, it was shown for antibodies that the consideration of the V H /V L angles for homology modeling can increase the accuracy considerably [ 41 , 48 , 49 ]. In this context, Dunbar et al identified key structural parameters, which provide a comprehensive description of the movement of the V H and V L domains with respect to each other [ 41 ].…”