Antibody structure determination using a combination of homology modeling, energy‐based refinement, and loop prediction

Abstract

We present the blinded prediction results in the Second Antibody Modeling Assessment (AMA-II) using a fully automatic antibody structure prediction method implemented in the programs BioLuminate and Prime. We have developed a novel knowledge based approach to model the CDR loops, using a combination of sequence similarity, geometry matching, and the clustering of database structures. The homology models are further optimized with a physics-based energy function (VSGB2.0), which improves the model quality significantly. H3 loop modeling remains the most challenging task. Our ab initio loop prediction performs well for the H3 loop in the crystal structure context, and allows improved results when refining the H3 loops in the context of homology models. For the 10 human and mouse derived antibodies in this assessment, the average RMSDs for the homology model Fv and framework regions are 1.19 Å and 0.74 Å, respectively. The average RMSDs for five non-H3 CDR loops range from 0.61 Å to 1.05 Å, and the H3 loop average RMSD is 2.91 Å using our knowledge-based loop prediction approach. The ab initio H3 loop predictions yield an average RMSD of 1.28 Å when performed in the context of the crystal structure and 2.67 Å in the context of the homology modeled structure. Notably, our method for predicting the H3 loop in the crystal structure environment ranked first among the seven participating groups in AMA-II, and our method made the best prediction among all participants for seven of the ten targets.

Cysteinylation of a monoclonal antibody leads to its inactivation

“…This method has been shown to be effective in describing antibody CDR structures. 26 Thus, modeling of the antibody 001 CDR domains was employed. As seen in Fig.…”

AcrB-AcrA Fusion Proteins That Act as Multidrug Efflux Transporters

“…The missing region of the AcrA structure was generated by using the SWISS-MODEL homology-modeling server and used to represent the whole structure of AcrA. The AcrA binding site was calculated by using the BioLuminate program in the Schrödinger suite (54). …”

Large-scale sequence and structural comparisons of human naive and antigen-experienced antibody repertoires

“…Although repertoire-wide crystallographic studies are not feasible at present, advances in computational protein modeling have enabled the structure of antibodies having moderate-length CDR loops to be predicted accurately (23)(24)(25)(26). In particular, computational models using RosettaAntibody-predicted X-ray structures within 1-1.5 Å rmsd in framework and canonical loops and 2 Å in CDR-H3 loops (27).…”