RESUMEN

In recent years, intracellular biophysical simulations have been used with increasing frequency not only for answering basic scientific questions but also in the field of synthetic biology. However, since these models include networks of interaction between millions of components, they are extremely time-consuming and cannot run easily on parallel computers. In this study, we demonstrate for the first time a novel approach addressing this challenge by using a dedicated hardware designed specifically to simulate such processes. As a proof of concept, we specifically focus on mRNA translation, which is the process consuming most of the energy in the cell. We design a hardware that simulates translation in Escherichia coli and Saccharomyces cerevisiae for thousands of mRNAs and ribosomes, which is in orders of magnitude faster than a similar software solution. With the sharp increase in the amount of genomic data available today and the complexity of the corresponding models inferred from them, we believe that the strategy suggested here will become common and can be used among others for simulating entire cells with all gene expression steps.

Asunto(s)

Computadores , Biosíntesis de Proteínas , Biosíntesis de Proteínas/genética , ARN Mensajero/genética , ARN Mensajero/metabolismo , Ribosomas/genética , Ribosomas/metabolismo , Programas Informáticos

RESUMEN

Fertilization of sea urchin eggs involves an increase in protein synthesis associated with a decrease in the amount of the translation initiation inhibitor 4E-BP. A highly simple reaction model for the regulation of protein synthesis was built and was used to simulate the physiological changes in the total 4E-BP amount observed during time after fertilization. Our study evidenced that two changes occurring at fertilization are necessary to fit with experimental data. The first change was an 8-fold increase in the dissociation parameter (koff1) of the eIF4E:4E-BP complex. The second was an important 32.5-fold activation of the degradation mechanism of the protein 4E-BP. Additionally, the changes in both processes should occur in 5 min time interval post-fertilization. To validate the model, we checked that the kinetic of the predicted 4.2-fold increase of eIF4E:eIF4G complex concentration at fertilization matched the increase of protein synthesis experimentally observed after fertilization (6.6-fold, SD = 2.3, n = 8). The minimal model was also used to simulate changes observed after fertilization in the presence of rapamycin, a FRAP/mTOR inhibitor. The model showed that the eIF4E:4E-BP complex destabilization was impacted and surprisingly, that the mechanism of 4E-BP degradation was also strongly affected, therefore suggesting that both processes are controlled by the protein kinase FRAP/mTOR.