LassoHTP: a High-throughput Computational Tool for Lasso Peptide Structure Construction and Modeling

Lasso peptides are a sub-class of ribosomally synthesized and post-translationally modified peptides with a slipknot conformation. Often with superior thermal stability, protease resistance, and antimicrobial activity, lasso peptides are promising candidates for bioengineering and pharmseutical applications. To enable high-throughput computational prediction and design of lasso peptides, we developed software, LassoHTP, for automatic lasso peptide structure construction and modeling. LassoHTP consists of three modules, including: scaffold constructor, mutant generator, and molecular dynamics (MD) simulator. Based on a user-provided sequence and conformational annotation, LassoHTP can either generate the structure and conformational ensemble as is or conduct random mutagenesis. We used LassoHTP to construct eight known lasso peptide structures de novo and to simulate their conformational ensembles from 100 ns MD simulations. For benchmarking, we calculated the root mean square deviation (RMSD) of these ensembles with reference to their experimental crystal or NMR PDB structures; we also compared these RMSD values against those of the MD ensembles that are initiated from the PDB structures. The results show that the RMSD values of the LassoHTP-initiated ensembles are highly similar to those of the PDB-initiated ensembles with the ∆RMSD ranging from 0.0 to 1.2 Å and averaging at 0.5 Å. LassoHTP offers a computational platform to develop strategies for lasso peptide prediction and design.