Mapping of antibody epitopes based on docking and homology modeling.

Antibodies are key proteins produced by the immune system to target pathogen proteins termed antigens via specific binding to surface regions called epitopes. Given an antigen and the sequence of an antibody the knowledge of the epitope is critical for the discovery and development of antibody based therapeutics. In this work, we present a computational protocol that uses template-based modeling and docking to predict epitope residues. This protocol is implemented in three major steps. First, a template-based modeling approach is used to build the antibody structures. We tested several options, including generation of models using AlphaFold2. Second, each antibody model is docked to the antigen using the fast Fourier transform (FFT) based docking program PIPER. Attention is given to optimally selecting the docking energy parameters depending on the input data. In particular, the van der Waals energy terms are reduced for modeled antibodies relative to x-ray structures. Finally, ranking of antigen surface residues is produced. The ranking relies on the docking results, that is, how often the residue appears in the docking poses' interface, and also on the energy favorability of the docking pose in question. The method, called PIPER-Map, has been tested on a widely used antibody-antigen docking benchmark. The results show that PIPER-Map improves upon the existing epitope prediction methods. An interesting observation is that epitope prediction accuracy starting from antibody sequence alone does not significantly differ from that of starting from unbound (i.e., separately crystallized) antibody structure.

Protein-Protein and Protein-Peptide Docking with ClusPro Server.

The process of creating a model of the structure formed by a pair of interacting molecules is commonly referred to as docking. Protein docking is one of the most studied topics in computational and structural biology with applications to drug design and beyond. In this chapter, we describe ClusPro, a web server for protein-protein and protein-peptide docking. As an input, the server requires two Protein Data Bank (PDB) files (protein-protein mode) or a PDB file for the protein and a sequence for the ligand (protein-peptide mode). Its output consists of ten models of the resulting structure formed by the two objects upon interaction. The server typically produces results in less than 4 h. The server also provides tools (via "Advanced Options" list) for a user to fine-tune the results using any additional knowledge about the interaction process, e.g., small-angle X-ray scattering (SAXS) profile or distance restraints.