Figure 3.

Design framework and application of LassoHTP. (a) A schematic of LassoHTP’s workflow, which involves three modules: scaffold constructor, peptide mutant generator, and MD simulator, to transform a user-input sequence into a conformational ensemble. (b) Application of the mutant generator module to convert the poly alanine lasso peptide scaffold into the lasso peptide that is consistent with the user-input sequence. Sequence shown is for xanthomonin-II¹⁰⁵ (PDB ID: 2MFV). (c) Distribution of root-mean-square deviation (RMSD) for LassoHTP-initiated and PDB-initiated MD conformational ensemble for caulosegnin-II.⁹⁸ (d) Average RMSD values of LassoHTP (LHTP)-initiated (colored in blue) and PDB-initiated (colored in orange) MD ensembles for eight lasso peptides involved in the benchmark. The structures of the lasso peptides were determined mostly by NMR except for caulosegnin-II by X-ray crystallography (PDB ID: 5D9E). For (c) and (d), the RMSD was calculated using backbone atoms (i.e., C_α, N, C, and O) with reference to the reference crystal and NMR structure. Adapted with permission from ref (57). Copyright 2023 American Chemical Society.