Freiburg researchers deliver new insights into molecular mechanisms relevant for drug development
Molecular dynamics simulations (MD) have become an ubiquitous tool in modern life sciences. In these simulations, the interactions between atoms and molecules and their resulting spatial movements are iteratively calculated and analyzed. Scientists are currently trying to gain access to biologically relevant length and time scales using this approach in order to describe molecular processes such as protein folding and protein-drug binding, which are crucial for, for example modern drug development.
In order to achieve the simplification of system dynamics, physicists have developed the dissipation-corrected targeted Molecular dynamics simulations. Credit: Steffen Wolf/AG Gerhard Stock
A team led by Dr. Steffen Wolf and Prof. Dr. Gerhard Stock from the Biomolecular Dynamics group at the Institute of Physics of the University of Freiburg has now succeeded in predicting the dynamics of binding and unbinding processes on a time scale of seconds to half a minute in pharmacologically relevant test systems. The results have been presented in the current issue of the journal Nature Communications.
Due to the need to perform atomistic simulations with a temporal resolution of femtoseconds (10-15 s), researchers are not yet able to explicitly calculate processes that take a few or more seconds, such as the binding and release of drugs to and from their respective target protein.
One possible approach to speed up simulations is coarse-graining of the overall system dynamics, which is a domain of non-equilibrium statistical mechanics. To achieve this coarse-graining, slow processes such as protein-ligand diffusion and fast processes like protein vibrations or water fluctuations must exhibit a clear time scale separation.
Only then can scientists use the Langevin equation, a stochastic differential equation that describes the dynamics along the relevant slow degrees of freedom - that is, the number of independent possibilities of movement -- of a physical system. Using this equation, they represent the dynamics of the system along a reaction coordinate such as the distance of the ligand from its binding site. All other, faster movements are considered as friction.
In order to achieve this necessary simplification of system dynamics, the Freiburg physicists have developed the dissipation-corrected targeted MD (dcTMD) using computational resources from the HPC cluster BinAC at the University of Tübingen.
By applying a constraining force to actively pull a microscopic system along a coordinate of interest, the required work can be broken down into free energy and friction fields of the process.
In the current publication, the researchers have shown that these dcTMD fields can be used as input for a simulation of the Langevin equation along the pulling coordinate. As a result, the researchers have been able to greatly reduce the required computational power. A simulation time of one millisecond can thus be achieved within a few hours on a single computing core of a standard desktop computer.
In addition, Langevin fields, explains Stock, do not change their structure at higher temperatures, unlike to atomistically described proteins. “Therefore, high-temperature simulations can produce accelerated dynamics. We can use this acceleration to extrapolate the dynamics at a lower temperature of interest, where the fields are derived from targeted MD simulations.”
The Freiburg scientists used the dissociation of sodium chloride and two protein-ligand complexes as test systems. In these they succeeded in predicting the dynamics of binding and unbinding processes on a time scale of seconds to half a minute.
“While the Langevin fields were only generated from unbinding simulations, they were able to predict both unbinding and binding kinetics within a factor 20 and dissociation constants within a factor 4, which is within the best achievable results compared to other prediction methods,” explains Wolf. At the same time, the new dcTMD approach requires only one tenth of the computing power of other prediction methods.
“Last but not least, the determination of friction profiles provides insights into molecular processes that are not revealed by free energy,” say the Freiburg physicists. “We found that in all the systems investigated, the formation of a hydration shell from water molecules seems to be the main source of friction. This enables us to deduce new rules for the design of drugs with desired binding and diffusion kinetics.”
Wolf, S., Lickert, B., Bray, S., Stock, G. (2020): Multisecond ligand dissociation dynamics from atomistic simulations. In: Nature Communications. DOI: 10.1038/s41467-020-16655-1
Dr. Steffen Wolf and Prof. Dr. Gerhard Stock
Institute of Physics
University of Freiburg
E-Mail: email@example.com; firstname.lastname@example.org
Nicolas Scherger | idw - Informationsdienst Wissenschaft
Rising water temperatures could endanger the mating of many fish species
03.07.2020 | Alfred-Wegener-Institut, Helmholtz-Zentrum für Polar- und Meeresforschung
Moss protein corrects genetic defects of other plants
03.07.2020 | Rheinische Friedrich-Wilhelms-Universität Bonn
Solar cells based on perovskite compounds could soon make electricity generation from sunlight even more efficient and cheaper. The laboratory efficiency of these perovskite solar cells already exceeds that of the well-known silicon solar cells. An international team led by Stefan Weber from the Max Planck Institute for Polymer Research (MPI-P) in Mainz has found microscopic structures in perovskite crystals that can guide the charge transport in the solar cell. Clever alignment of these "electron highways" could make perovskite solar cells even more powerful.
Solar cells convert sunlight into electricity. During this process, the electrons of the material inside the cell absorb the energy of the light....
Empa researchers have succeeded in applying aerogels to microelectronics: Aerogels based on cellulose nanofibers can effectively shield electromagnetic radiation over a wide frequency range – and they are unrivalled in terms of weight.
Electric motors and electronic devices generate electromagnetic fields that sometimes have to be shielded in order not to affect neighboring electronic...
A promising operating mode for the plasma of a future power plant has been developed at the ASDEX Upgrade fusion device at Max Planck Institute for Plasma...
Live event – July 1, 2020 - 11:00 to 11:45 (CET)
"Automation in Aerospace Industry @ Fraunhofer IFAM"
The Fraunhofer Institute for Manufacturing Technology and Advanced Materials IFAM l Stade is presenting its forward-looking R&D portfolio for the first time at...
With an X-ray experiment at the European Synchrotron ESRF in Grenoble (France), Empa researchers were able to demonstrate how well their real-time acoustic monitoring of laser weld seams works. With almost 90 percent reliability, they detected the formation of unwanted pores that impair the quality of weld seams. Thanks to a special evaluation method based on artificial intelligence (AI), the detection process is completed in just 70 milliseconds.
Laser welding is a process suitable for joining metals and thermoplastics. It has become particularly well established in highly automated production, for...
02.07.2020 | Event News
19.05.2020 | Event News
07.04.2020 | Event News
03.07.2020 | Life Sciences
03.07.2020 | Studies and Analyses
03.07.2020 | Power and Electrical Engineering