Single Atom Replacement Might Speed up Insulin Availability

Researchers recommend that a small chemical modification to insulin can make the molecule act more quickly while protecting its function in the organism. In the Journal of Biological Chemistry, investigators explain how they predicted the effect with computer simulations and then confirmed it with laboratory studies.

Image credit: University of Basel Department of Chemistry
Image credit: University of Basel Department of Chemistry

Global scientist team identified that they could accelerate the disassembly and release of insulin from its complex structure to its available form by substituting a single hydrogen atom with an iodine atom in its molecular structure.

Insulin is a tiny protein that controls blood glucose by passing signals into cells. In the human body, it is present in two forms:

  • a complex one for storage and
  • a simpler one for action.

In its storage form, insulin exists as a zinc bound complex of six similar molecules known as a hexamer. The simple, active form is an unbound single molecule, or monomer.

When the body needs insulin to regulate blood sugar, the hexamer disassembles into monomers.

The insulin molecule then has to combine to a partner molecule – recognized as the insulin receptor – that is placed on the surface of cells. This binding enables signals from the insulin to pass into the cell.

For some time, investigators have been testing with ways to control this disassembly process to enhance the therapy of diabetes, a condition that takes place when insulin production is reduced or when the body cannot use it effectively.

Protein engineering

Investigators use different techniques to discover new ways to fight disease with molecules that do not exist in nature. This involves developing synthetic versions, or analogs, of naturally occurring compounds.

Protein engineering consists of modifying the structure and function of proteins – the chemical workhorses of the organism – using only a computer or via evolution in the lab.

One area of application that is demonstrating promise is the development of designer medicines to protect against various strains of influenza virus.

In the new study, Markus Meuwly and colleagues experimented with different insulin analogs by tactically replacing individual atoms in the molecular structure of natural insulin.

Promising method for enhancing medicinal compounds.

Computer simulations depending on quantum chemistry and molecular dynamics, which model processes in the body involving insulin, permitted the team to notice the properties of the analogs.

Study team then performed laboratory experiments to ensure the properties noticed in the computer simulations. These studies used methods like as crystallography and nuclear magnetic resonance.

The investigators identified that substituting one hydrogen atom for one iodine atom enhanced the availability of insulin but did not change its affinity for the insulin receptor.

It is quite possible, say the investigators, that their insulin analog – which is different from natural insulin by only a single atom – has clinical potential as a new medicine.

The use of halogen atoms – a group that contains fluorine, chlorine, bromine, and iodine – is a promising method for optimizing compounds in medicinal chemistry, say the investigators.

Add to above statement investigators said,

“Inspired by quantum chemistry and molecular dynamics, like ‘halogen engineering’ assures to expand principles of medicinal chemistry to proteins.”