Year: 2024
Type: article
Abstract: Lasso peptides are a class of natural products characterized by a threaded structure. Given their small size and stability, chemical synthesis would offer tremendous potential for the development of novel therapeutics. However, the accessibility of the pre-folded lasso architecture has limited this advance. To better understand the folding process de novo, simulations are used herein to characterize the folding propensity of microcin J25 (MccJ25), a lasso peptide known for its antimicrobial properties. New algorithms are developed to unambiguously distinguish threaded from non-threaded precursors and determine handedness, a key feature in natural lasso peptides. We find that MccJ25 indeed forms right-handed pre-lassos, in contrast to past predictions but consistent with all natural lasso peptides. Additionally, the native pre-lasso structure is shown to be metastable prior to ring formation but to readily transition to entropically-favored unfolded and non-threaded structures, suggesting de novo lasso folding is rare. However, by modifying the ring forming residues with the appendage of thiol and thioester functionalities, we are able to increase the stability of pre-lasso conformations. Furthermore, conditions leading to protonation of a histidine imidazole side chain further stabilize the modified pre-lasso ensemble. This work highlights the use of computational methods to characterize lasso folding and demonstrates that de novo access to lasso structures can be facilitated by optimizing sequence, unnatural modifications, and reaction conditions like pH.
DOI: 10.1021/jacs.3c10126
Institution: University of Utah
Language: English
Subfield: Molecular Biology
Domain: Life Sciences
Open Access status: green
Awards: G1323184041, Track 4: Advanced CI Coordination Ecosystem: Monitoring and Measurement Services, G2824220663, G3045716671, G34258105, G4275568664, ACO: An Open CI Ecosystem to Advance Scientific Discovery (OpenCI), G4881832910, Track 3: COre National Ecosystem for CyberinfrasTructure (CONECT), G5156331529, G682399897, G7526614437, Track 2: Customized Multi-tier Assistance, Training, and Computational Help (MATCH) for End User ACCESS to CI, G8499740153, G8867496530, Integrating Stochasticity into Biomolecular Mechanisms: A New Direction for Biomolecular Modeling
OpenAlex ID: W4390490178