The human body is always at work. Even while you’re asleep, thousands of biological processes are ongoing, providing you with energy to sustain life, oxygen to continue energy production and the materials to produce life. These and many other biological processes operate at a molecular level without the need for human control—and ligands and proteins regulate many of them.

Interactions Between Ligands and Large Proteins

A ligand is any substance or molecule that binds with a biological molecule to achieve a biological purpose. In the human body numerous ligands are at work, binding with biomolecules to allow natural processes to continue. In many cases, the ligands featured are large proteins.

During protein-ligand interactions, the ligand typically triggers a signal for a biological process to begin or continue. This signaling occurs when a ligand binds to a particular binding site on the protein. Currently, researchers in multiple fields—particularly pharmacology—rely on information regarding these molecular interactions to learn more about how biological processes can go wrong.

Molecular Dynamics Simulations

Many biopharmaceuticals are designed to interact with large proteins in the body in a similar way as the natural ligands do, thus altering, delaying, or eliminating the signals sent to spur biological processes to treat diseases. To develop these drugs, researchers must simulate protein-ligand interactions to model their effects.

Using supercomputers, molecular dynamics simulations portray a detailed overview of the way proteins and ligands interact. However, simulations focus only on a select few binding and unbinding interactions. In real life, ligands and proteins interact in multiple different ways. Currently, researchers are making an effort to extend the breadth of molecular dynamics simulations and include more interactions in each study.

New Methods

Heading up this effort are researchers at the RIKEN Center for Biosystems Dynamics Research. Using a technique called replica-exchange molecular dynamics, the RIKEN Center has successfully extended molecular dynamics simulations to simulate hundreds of binding events, and the unbinding events that follow. The team’s first project simulated an interaction between a protein kinase and an inhibitor and featured over 100 binding and unbinding events. The interaction took about a month to simulate, a stark contrast to the near-year simulations taken using current methods.

When the group debuts its new supercomputer at the beginning of 2021, researchers expect even quicker simulations, which will take mere days instead of the month the kinase-inhibitor interaction required with the current computer.

Moving Forward

As the use of the new simulations continues, researchers anticipate a dramatic increase in knowledge about the events that occur early in the binding interaction. Developments in these early stages can dramatically affect the way future interactions occur, and early-bound states have the potential to influence the way drugs are designed. Eventually, the RIKEN Center team hopes to be able to study drug development as it occurs in a living cell. This could dramatically speed up the development of essential therapies for many devastating diseases. The adaptation of supercomputer molecular dynamics simulations could provide a crucial first step.

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