A new type of friction is discovered in the protein-ligand system

March 31, 2023

(Nanowerk News) An interdisciplinary research team from the University of Freiburg’s Institute of Physical Chemistry and Physics and the Max Planck Institute of Biophysics in Frankfurt-am-Main have discovered a new direction-dependent friction in proteins called anisotropic friction.

“Until now, no one has observed that friction in biomolecules is direction dependent,” said physicist Dr. Steffen Wolf of the University of Freiburg.

The results have been published as cover stories in scientific journals Nano Letters (“Anisotropic Friction in Ligand-Protein Complexes”). Interesting experiments on the biotin-streptavidin complex. Biotin (blue line) is pulled out of the streptavidin protein (yellow) via a polymer link (gray line), which is attached to the end of an atomic microscope support (grey triangle). (Image: Dr. Steffen Wolf)

Experiments on models of protein-ligand complexes

Proteins are the microscopic machinery of the cell. They perform work during their functional cycle. Thus, they follow the laws of thermodynamics, exhibit efficiency of energy conversion, and lose energy during their functional cycle due to dissipation. From a macroscopic perspective, the latter effect is related to visible friction. On the microscopic scale of a single protein, a known source of friction is the internal friction of the protein resulting from the excitation of the protein’s internal vibrations. A further source is solvent friction, which arises from the acceleration of the surrounding solvent molecules.

This friction source causes heating of the protein and solvent. Here, the researchers discovered a new type of friction by performing single-molecule experiments and simulations on complex models of proteins and ligands.

In their single molecule experiment, the team used a new method that employs stereographic single molecule force spectroscopy, which is based on atomic force microscopy (AFM). This technique allowed them to study the ligand unbinding of a protein bound to a surface not only along one coordinate, but along all three Cartesian coordinates. During their experiments, Dr. Wanhao Cai, Prof. Dr. Thorsten Hugel and Dr. Bizan N. Balzer from the Institute of Physical Chemistry at the University of Freiburg and Dr. Jakob T. Bullerjahn of the Max Planck Institute, made the surprising discovery that friction during ligand unbinding increases with the angle of attraction applied.

Combine experiments and computer simulations

Miriam Jäger and Dr. Steffen Wolf of the University of Freiburg’s Institute of Physics then recreated the experiment using computer simulations. They use high performance computing (HPC) resources from the BinAC-HPC-Cluster in Tübingen. During the simulations they determined that the work of releasing a ligand from its binding site depended on the proper direction of application of the tensile force.

By combining the results from the experiments and simulations, the researchers recognized that the source of the angle-dependent friction was the indeterminate and random orientation of the proteins along the axis of rotation bound to the surface in the experiment. The team repeated the single-molecule withdrawal experiment by binding and releasing ligands to and from the protein many times to achieve statistically significant results. There, the ligand binds to a different protein for each measurement.

Consequently, in each measurement, the ligands are pulled at the same angle to the surface, but at different regions of the protein in a randomly oriented manner. This orientation is undefined, neither in an experimental setting nor in the real world, and every measurement is not exactly repeatable and reversible. Hence, each time a different amount of energy is deposited into the biomolecules. The irreversible part of this energy is lost as heat to the system. The corresponding effect is a source of friction, which the researchers call anisotropic friction.

Fundamental friction type

“We assume that this previously unknown and fundamental type of friction is present in any bioassembly where randomness in the orientation of the protein occurs together with the direction of application of force,” says Dr. Bizan N. Balzer, a biophysicist. He explains that this is the case for biomolecular motors or force-sensitive membrane proteins, as well as for processes such as blood flow, where forces are exerted on randomly oriented proteins. Balzer concludes, “Anisotropic friction is thus an important piece of the puzzle for understanding friction in both technical applications and in biological complexes in general.”

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