RESEARCH: CANCER
FOLDING PROJECT #18913 PROFILE

Lasso peptides are special proteins that can fight cancer and infections. This project will use computer simulations to figure out how these peptides are made, especially the step where they form their unique shape.

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, 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 with cyclase enzyme to explore lasso peptide cyclization mechanism.

Lasso peptides

Ribosomally synthesized and post-translationally modified peptides with a unique lariat-like conformation.

Lasso peptides are a type of natural product made by bacteria. They have a distinctive loop structure and can interact with human cells. Scientists are studying them for their potential as new drugs because they show promise in fighting cancer, bacteria, and viruses.

RiPP

Ribosomally synthesized and post-translationally modified peptides

RiPP stands for Ribosomally Synthesized and Post-translationally Modified Peptides. These are natural products made by bacteria that have a unique structure and often show biological activity.

Macrolactam ring

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

A macrolactam ring is a large, circular molecule formed when a carboxylic acid and an amine group react. This type of structure is found in lasso peptides.

Isopeptide bond

A covalent bond between the carboxyl group of one amino acid and the side chain amino group of another amino acid.

An isopeptide bond is a special type of chemical link between amino acids. It's different from regular peptide bonds because it connects to an amino group on the side chain of an amino acid, not just the main chain.

Molecular Dynamics simulations

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

Molecular Dynamics simulations are like virtual experiments. Scientists use computers to create models of molecules and then watch how they move and interact over time. This helps us understand how things work at the atomic level.