RESEARCH: CANCER
FOLDING PROJECT #18930 PROFILE

Lasso peptides are unique antibiotic molecules shaped like a lasso. Scientists want to understand how these peptides are made so they can develop new drugs. This project uses computer simulations to explore the structure and formation of lasso peptides and the enzymes that help create them.

Lasso peptides are ribosomally synthesized and post-translationally modified peptide (RiPP) natural products that display a unique lariat-like, threaded conformation.

Some lasso peptides have been shown to bind human cell-surface receptors and exhibit anticancer properties, while others display antibacterial or antiviral bioactivities.

So studies on the lasso peptide synthesis will significantly facilitate the discovery and application of new drugs. Specifically, previous studies show that the unique lasso topology is formed by a macrolactam ring that is threaded by the C-terminal tail.

While not proven yet, the threading cannot occur after the ring formation.

The general proposed mechanism is that lasso peptide first form a prefolded lariat-like structure, then lasso peptide cyclase catalyzes the ring closure achieved by an isopeptide bond formed between the N-terminal α-amino group of a glycine, alanine, serine, or cysteine and the carboxylic acid side chain of an aspartate or glutamate, which can be located at positions 7, 8, or 9 of the amino acid sequence.

However, MD study on lasso peptide topology is very less and the detailed function of lasso peptide cyclase and the molecular mechanism of the whole lasso peptide cyclization process are not clear.

Therefore, in this study, we will perform Molecular Dynamic simulations for the system of lasso peptide or peptide with cyclase enzyme to explore lasso peptide topology and the cyclization mechanism.

Lasso peptides

Ribosomally synthesized and post-translationally modified peptide natural products with a unique lariat-like structure.

Lasso peptides are a type of naturally occurring molecule produced by bacteria. They have a distinctive loop-like shape and are being studied for their potential as new drugs due to their ability to fight cancer, bacteria, and viruses.

RiPP

Ribosomally synthesized and post-translationally modified peptides.

RiPP stands for Ribosomally Synthesized and Post-Translationally Modified Peptides. These are molecules produced by bacteria that have a unique structure and are being investigated for their potential as new drugs.

macrolactam ring

A large cyclic amide structure formed by the reaction of a carboxylic acid and an amine group.

A macrolactam ring is a large ring-shaped molecule found in some proteins. It's formed when a carboxylic acid group reacts with an amino group, creating a stable bond.

lasso peptide cyclase

An enzyme that catalyzes the formation of the macrolactam ring in lasso peptides.

Lasso peptide cyclase is an enzyme responsible for creating the unique loop-like structure found in lasso peptides. It does this by linking specific parts of the molecule together.

Molecular Dynamic simulations

Computer simulations that model the movement of atoms and molecules over time.

Molecular Dynamic simulations are computer programs that allow scientists to study how molecules move and interact. They are used to understand the behavior of complex systems like proteins and DNA.