Limitations of the ABEGO-based backbone design: ambiguity between αα-corner and αα-hairpin.

Abstract

ABEGO is a coarse-grained representation for poly­peptide backbone dihedral angles. The Ramachandran map is divided into four segments denoted as A, B, E, and G to represent the local conformation of poly­peptide chains in the character strings. Although the ABEGO representation is widely used in backbone building simulation for de novo protein design, it cannot capture minor differences in backbone dihedral angles, which potentially leads to ambiguity between two structurally distinct fragments. Here, I show a nontrivial example of two local motifs that could not be distinguished by their ABEGO representations. I found that two well-known local motifs αα-hairpins and αα-corners are both represented as α-GBB-α and thus indistinguishable in the ABEGO representation, although they show distinct arrangements of the flanking α-helices. I also found that α-GBB-α motifs caused a loss of efficiency in the ABEGO-based fragment-assembly simulations for de novo protein backbone design. Nevertheless, I was able to design amino-acid sequences that were predicted to fold into the target topologies that contained these α-GBB-α motifs, which suggests such topologies that are difficult to build by ABEGO-based simulations are designable once the backbone structures are modeled by some means. The finding that certain local motifs bottleneck the ABEGO-based fragment-assembly simulations for construction of backbone structures suggests that finer representations of backbone torsion angles are required for efficiently generating diverse topologies containing such indistinguishable local motifs.