Fig. 3.

Geometric corrections improve topological features of the designed structures. (A) Overview of the naive and native-like TopoBuilder design pipeline. The developed pipeline includes a topological correction step rendering a naive sketch into a native-like structure with improved designability. Full atomistic models are generated through the Rosetta fragment assembly protocol (Rosetta FunFolDes), sequences are designed using the Rosetta FastDesign method and state-of-the-art protein structure prediction methods (trRosetta and AlphaFold) are used to assess the design quality. (B) The native-like sketches of the example folds with three of the geometric parameters indicated. (C) Distributions of the ζ-correction parameter computed from the retrieved matches. The ζ-correction parameter captures features related to the orientation of the different layers. (D) Distributions of ɛ-correction parameter computed from the retrieved matches. The ɛ-correction parameter captures features related to the orientation of the different layers. (E) Distributions of the d_z correction parameter computed from the retrieved matches. The d_z correction parameter captures the distance between layers in the sketch. (C–E) The native geometry distributions are shown in gray. In yellow, the output of simulations (1,000 decoys) using a naive sketch without correction of the SSEs, which tends to result in flat β-sheets and α-helical stackings. Shown in green are simulations (1,000 decoys) derived from native-like sketches where the outputs more closely follow the native distributions.