Major grant to research on the dynamic interactions between molecules
The interactions between molecules are the foundation of life and how we treat diseases using medicinal drugs. But what does it actually look like when a protein meets another molecule and binds to it? A new research project that has been awarded EUR 8.7 million by the European Research Council now aims to shed light on this elusive process. The research team consists of researchers from Lund University, Sweden, University of Copenhagen, Denmark, and University Medical Center Hamburg-Eppendorf, Germany.
Jessika Sellergren – Published 25 January 2023
Understanding how proteins function is vital — they are crucial for all processes that enable life. Proteins are molecules with a wide range of dynamic functions in the body, but knowledge about these functions is based mainly on models in which they are considered to be static structures.
“The idea that proteins are static molecules is incorrect — they make spontaneous transitions between different structural states. Some of these are rare and often invisible to traditional research methods,” says Mikael Akke, Professor of Biophysical Chemistry at Lund University, Sweden, who together with Kresten Lindorff-Larsen, Professor of Computational Protein Biophysics at the University of Copenhagen, Denmark, and Eike-Christian Schulz, research group leader in Biochemistry and Signal Transduction at the University Medical Center Hamburg-Eppendorf, Germany, will make use of this major grant in a six-year method-development project.
Their collaborative research will increase understanding of the processes taking place when a protein molecule binds to another molecule, and how long the binding lasts — knowledge that in the future could lead to improved medicines.
The molecule’s path — like a ball rolling down a mountain
In practical terms, the researchers will study how proteins from viruses such as HIV and SARS-CoV-2 bind ligands — molecules that come, for example, from medicines. The aim is to map how the structure and energy of protein and ligand change during the process.
Mikael Akke likens the process of a ligand binding to a protein in the body to rolling a ball down a mountain:
“If you release a ball at the top of a mountain, the ball will roll down, taking different paths at random, depending on the topography. Valleys and hills in the terrain may make the ball change course and speed, but ultimately it ends up in a hollow that brings it to a halt. If we picture the ball as the ligand, you could say that it stopped in a binding protein pocket.”
The researchers will map the ligand’s paths, what makes it get caught in a specific pocket and how long this takes. As the ligand can take several paths, all options need to be identified.
Combining several measurement methods is necessary
The three participating research teams use different methods to study the movement of the protein molecule and ligand during the binding process: nuclear magnetic resonance spectroscopy (Lund), time-resolved X-ray crystallography (Hamburg) and molecular simulations and other computational tools (Copenhagen).
“You could say that we are moving structural biology into a new era of protein dynamics in which it is necessary to combine our different methods in order to understand and quantify all the details. One method provides valuable information to the other, and through mutual exchange we can jointly contribute to the generation of completely new knowledge about how proteins and ligands interact,” says Kresten Lindorff-Larsen.
The final result can be compared to an advanced molecular movie describing the ligand’s path to the binding protein pocket.
“We hope to gain new insights into how long it takes for a medicinal drug molecule to bind to a protein in the body and how long the molecule remains there — knowledge that in the long term could lead to uniquely designed and more effective medicines,” concludes Eike-Christian Schulz.
DynaPLIX stands for Dynamics of Protein–Ligand Interactions. The project is funded through an ERC Synergy Grant of EUR 8.7 million over a six-year period. The project participants are: Professor Mikael Akke at the Division of Biophysical Chemistry, Center for Molecular Protein Science, Department of Chemistry, Lund University; Professor Kresten Lindorff-Larsen at the Linderstrøm-Lang Centre for Protein Science, Department of Biology, University of Copenhagen; and Dr. Eike-Christian Schulz at the Center for Experimental Medicine, University Medical Center Hamburg-Eppendorf.
ERC Synergy Grant
The European Research Council (ERC) promotes researcher-driven research of the highest quality in all areas of science through extensive and long-term funding.
The ERC supports leading-edge research, multidisciplinary and interdisciplinary research projects and ground-breaking ideas in new and emerging areas.
ERC Synergy Grants are aimed at small teams of outstanding researchers who wish to collaborate on a joint research project.
Read more on the ERC website: ERC Synergy Grants 2022 - project highlights | ERC (europa.eu)