While interactions of biological molecules have been studied in depth, that work has not usually been done in the typical biological environment, which is usually the crowded interior of a cell. A report
from researchers at RIKEN and Michigan State University (MSU), published in the journal eLife aimed to use a supercomputer to reveal more about that molecular behavior in a realistic setting. A video from their publication, showing their system in atomistic detail; macromolecules are in both cartoon and lines, metabolites and ions are shown with stick or sphere, while the macromolecules in the background are shown with surface representation.
"Biological processes that make life happen and cause diseases largely take place inside cells, which can be studied with microscopes and other techniques, but not in enough detail," explained the study leader, Michael Feig, a Professor of Biochemistry and Molecular Biology at MSU. "Our research has revealed unprecedented details about what exactly takes place inside biological cells, and how proteins in particular behave in their natural environment."
The macromolecules inside of a cell make up about 30 percent of the volume, the remainder is the aqueous cytoplasm in which everything is suspended. A supercomputer at the RIKEN Advanced Institute for Computational Science in Kobe, Japan, was utilized to simulate how the various molecular parts of a cell interact in the interior of a bacterium, Mycoplasma genitalium. It may be the smallest known strain of bacteria, but the computer still needed to model roughly one trillion atoms of the cell. It took the supercomputer several months to complete the work despite using 65,536 processing cores.
"Our computer simulations were not too far away from simulating an entire cell in full atomistic detail," Feig commented. "These simulations exceeding 100 million atoms are the largest simulations of this kind and are several orders of magnitude larger than what is typical research work today."
The research indicated that the dense cellular environment may help molecules involved in similar functions come together, possibly to increase efficiency. The investigators discovered that very tight spatial conditions may decrease the stability of some proteins, illustrated in the video below.
The work suggests that influences like electrostatic forces may have an important role in molecular interactions, and not a phenomenon known as the volume exclusion effect - the prevailing theory that says when a molecule occupies a part of the solvent, it impacts other molecules by keeping them out of that space.
The first author of the study, Isseki Yu of RIKEN iTHES said, "This work has shown us that there are major differences between in vitro conditions and the in vivo conditions in the cell. We have found evidence for interactions beyond the 'volume exclusion effect', including protein-protein interactions and electrostatic interactions with ions and metabolites. These need to be taken into effect when interpreting in vitro studies."
"This research has brought us one step closer to the dream of simulating a complete cell at the molecular scale. The work will also contribute to drug development, as previous studies usually looked at interactions between proteins and a single candidate compound within water. Now, we will be able to also analyze the interactions between the candidate compound and other molecules within the crowded cellular environment," said Yuji Sugita, who has laboratories in iTHES as well as the RIKEN Quantitative Biology Center and RIKEN Advanced Institute for Computational Science. "One limitation of this study is that because of the enormous computing power required, we were only able to conduct short simulations. We believe it is still accurate, but hope to be able to perform this work on even more powerful future computers to reduce the statistical uncertainties and incorporate other interactions into the simulation such as genomic DNA and cytoskeletal elements."
"Future studies will aim to reach longer time scales, and to move towards larger and more complex cells, especially human cells, to better relate to human diseases," Feig concluded.
If you'd like to know more about the K supercomputer, watch the above video.