The design and engineering of antibodies are primarily carried out via experimental methods such as hybridoma technology or synthetic library surface display ( Almagro et al., 2019). The binding domains of antibodies consist of two regions: a scaffold-like, highly-conserved framework region and hypervariable binding loops (i.e., complementarity determining regions (CDRs)) that interact with antigens ( Pantazes and Maranas, 2010). Antibodies have become the most important type of binding protein, with a global therapeutic market value of over $100 billion ( Lu et al., 2020), and their structures have been extensively studied ( Ducancel and Muller, 2012). Their roles include performing catalysis by binding to substrates as enzymes ( Vaissier Welborn and Head-Gordon, 2019), transporting ligands across cell membranes as carrier and channel proteins ( Barabote et al., 2006), and antibodies binding to foreign antigens to tag them for destruction by vertebrate immune systems ( Lu et al., 2020). This work contributes to the discovery of novel binders based on smaller-sized, fixed-backbone protein scaffolds.īinding proteins are an integral part of innumerable biological processes. The top MutDock poses consisted of higher and comparable binding energies than the top ZDOCK and HADDOCK poses, respectively. The energies of the docked poses were minimized and binding energies were compared with docked poses from ZDOCK and HADDOCK. MutDock was used to dock two scaffolds, namely, Affibodies and DARPins, with ten randomly selected antigens. The second step mutates clashing variable interface residues and thermodynamically unfavorable residues to create additional strong interactions. This step considers both native and mutated rotamers of scaffold residues. The first step uses pairwise distance alignment of hydrogen bond-forming areas of scaffold residues and compatible epitope atoms. The approach is broadly divided into two steps. In this work, we have developed MutDock, a novel computational approach that simultaneously docks and mutates fixed backbone scaffolds for binding a target epitope by identifying a minimum number of hydrogen bonds. Docking fixed-backbone scaffolds with a varied group of surface amino acids increases the chances of identifying superior starting poses that can be improved with subsequent mutations. The commonly used dock-and-mutate approach for binding proteins, including antibodies, is limited because it uses a constant sequence and structure representation of the scaffold. While the computational design of antibodies for target epitopes has been explored in depth, the same has not been done for alternative scaffolds. A subset of these alternative scaffolds recognizes target molecules through mutations to a set of surface resides, which does not alter their backbone structures. Alternative binding scaffolds of smaller size have been developed to overcome these issues. Chemical Engineering Department, Auburn University, Auburn, AL, United Statesĭespite the successes of antibodies as therapeutic binding proteins, they still face production and design challenges.
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