Cell membranes in silico
Modeling of cell membranes will help predict the effects of drugs and poisons
Scientists have created a modeling method capable of describing the "responses" of cell membranes to drug and toxin molecules with high accuracy and relatively quickly, which will allow calculating the effect of drugs on cells in advance, without any experiments, according to a MIPT press release.
"The peculiarity of our method is that it provides a complete numerical description of changes in the molecule. We can track the position of all atoms at once, and each variant of the structure is assigned a value that can be used for statistical analysis," says lead author of the study Ivan Gushchin, head of the Laboratory for Structural Analysis and Engineering of Membrane Systems, established at the Center for Research on Molecular Mechanisms of Aging and Age–Related Diseases at MIPT.
It is extremely difficult to model the behavior of biological molecules, since it is necessary to describe the movement of each of its atoms – even for a small molecule of 54 atoms, 156 sets of numbers will be obtained. Huge amounts of information obtained as a result of modeling are difficult and time-consuming to process and interpret.
The group led by Gushchin found a way to significantly simplify the analysis of the simulation results, while almost losing the accuracy of the description of the movement. The authors of the study used the main component method for processing outgoing data – a processing method that highlights the most significant data from the data. This reduced the amount of data by 10 times, and the accuracy decreased by only 10%. The method was tested on the lipid molecule DOPC (dioleoyl phosphatidylcholine), well studied experimentally.
The structure of the DOPC molecule studied by the authors. On the left – the chemical structure of the molecule, on the right – the possible positions of the molecule in space. Image courtesy of the authors of the study.
Eight different force fields – sets of parameters for describing the interaction of all atoms - were chosen for modeling. Some force fields describe the interactions between atoms in great detail, others – roughly and approximately. After that, the authors applied the principal component method to the obtained data. It turned out that to describe the movement of a molecule of 54 atoms, only 14 "components" are enough, that is, the joint movements of a group of atoms in a molecule. One of the components, for example, is responsible for the movement of two "tails" of the DOPC molecule in different directions, like scissors.
Two variants of the main components of the motion of the molecule. "Compact" and "expanded" structures are shown in red and blue, respectively, intermediate structures are shades of purple. Image courtesy of the authors of the study.
The cell membrane is built from lipid molecules, and any molecules must overcome it in order to act on the cell. Therefore, studying the behavior of lipids with accuracy to individual atoms will help predict the effect of drugs, toxins on cells and the body as a whole, and therefore significantly accelerate the search for new drugs and drug testing. In addition, modeling can help in the study of aging processes, the mechanism of which, according to some assumptions, is associated with changes in the structure of cell membranes.
The study was published in the Journal of Chemical Theory and Information (Buslaev et al., Principal Component Analysis of Lipid Molecule Conformational Changes in Molecular Dynamics Simulations).
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26.04.2016