Accurate to the atom and nanosecond

Scientists have modeled the intracellular environment at the atomic level

Oleg Lischuk, N+1

Japanese and American scientists have built a computer simulation of the intracellular environment at the atomic level with nanosecond resolution. The results of the work are published in the journal eLife (Yu et al., Biomolecular interactions modulate macromolecular structure and dynamics in an atomic model of a bacterial cytoplasm).

The structure and dynamics of biological macromolecules, such as proteins and nucleic acids, have been studied quite well in vitro. However, such experiments give insufficient insight into how different molecules behave and interact with each other in crowded conditions of the intracellular environment (it consists of 25-45 percent of macromolecules, less than one percent of metabolites, the rest is water). The most widespread hypothesis is that the main effect on macromolecules in the cell is the effect of displaced volume. It consists in the fact that any macromolecule reduces the volume of solvent available to other macromolecules, which increases their effective concentration, i.e. chemical activity (see Fig.). However, the exact "alignment of forces" within the cells as a whole remains unclear.

Volume of available solvent (red) for molecules of different sizes
(black) in a close environment of macromolecules (gray).
Wikimedia Commons.

Employees of the RIKEN Institute and the University of Michigan conducted a computer simulation of the cytoplasm of one of the smallest (about 0.4 micrometers in diameter) known bacteria — genital mycoplasma (Mycoplasma genitalium). This dynamic model contains proteins, nucleic acids (including ribosomes), metabolites, ions and water, consisting of individual atoms (as stated in the press release, the total number of atoms of the model is about a trillion). To create it, scientists used the GENESIS parallel molecular dynamics algorithm of their own design, which they launched on a 65536-core supercomputer K.

The behavior of the molecules in the model was compared with the simulation of the same molecules in a dilute solution. Analysis of the data showed that the displaced volume effect does not play as significant a role as previously thought. Protein-protein interactions due to electrostatic and van der Waals forces, as well as the opposite effect of macromolecule hydration, were of great importance. Electrostatic interactions of proteins with charged metabolites (such as ATP) and ions also played a significant role.

Analysis of the interaction between different classes of macromolecules revealed significant electrostatic repulsion between different RNA molecules, as well as RNA and large molecular complexes, primarily ribosomes. The repulsion between proteins and RNA or ribosomes was significantly weaker. Glycolytic (glucose-splitting) enzymes, on the contrary, showed weak attraction. It corresponds to experimental data on the formation of dynamic complexes to increase the efficiency of multistage reactions (such as glycolysis) by rational distribution of substrate flows.

"Our work has revealed large differences between the conditions in the test tube and in a living cell. We have obtained evidence of interactions beyond the displaced volume effect, including protein-protein and electrostatic interactions with ions and metabolites. This should be taken into account when interpreting the results of in vitro studies," explained Isseki Yu, the author of the study.

Scientists expect to confirm and refine the results obtained in the future using more powerful supercomputers, which will increase the time and volume of the dynamic model, as well as include chromosomal DNA and cytoskeleton elements in it.

Modern technologies allow you to create models of living systems with the highest resolution. So, recently, the compatriots of Yu managed to simulate all the neuronal connections of one hemisphere of the brain of the fruit fly drosophila. And the staff of the Allen Institute for Brain Research has posted a full interactive atlas of the brain with micron resolution in open access.

Portal "Eternal youth" http://vechnayamolodost.ru 02.11.2016