RESEARCH: CANCER
FOLDING PROJECT #18925 PROFILE

Lasso peptides are special tiny proteins with unique shapes that can fight cancer and infections. Scientists want to understand how these shapes form so they can design new medicines. This project will use computer simulations to figure out the step-by-step process of how lasso peptides fold into their shapes.

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 conformation.

Lasso peptides are a type of naturally occurring molecule made by ribosomes and further modified after creation. They have a distinctive looping structure and have shown potential as anticancer, antibacterial, and antiviral agents.

RiPP

Ribosomally synthesized and post-translationally modified peptide

RiPP stands for ribosomally synthesized and post-translationally modified peptide. These are naturally occurring molecules produced by ribosomes and further modified after creation.

Macrolactam ring

A cyclic structure formed by the reaction of an amine group with a carboxylic acid group within a peptide chain.

A macrolactam ring is a large, ring-shaped structure found in certain peptides. It forms when a nitrogen atom (amine group) reacts with a carboxyl group (carboxylic acid), closing the peptide chain into a loop.

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 characteristic loop structure in lasso peptides. It facilitates a chemical reaction between specific parts of the peptide chain, forming the macrolactam ring.

Molecular Dynamic simulations

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

Molecular Dynamic simulations are computer programs that simulate how atoms and molecules move and interact. They help researchers understand complex biological processes and design new drugs.