Developing an Updated Strategy for Estimating the Free-Energy Parameters in RNA Duplexes

For the last 20 years, it has been common lore that the free energy of RNA duplexes formed from canonical Watson–Crick base pairs (bps) can be largely approximated with dinucleotide bp parameters and a few simple corrective constants that are duplex independent. Additionally, the standard benchmark set of duplexes used to generate the parameters were GC-rich in the shorter duplexes and AU-rich in the longer duplexes, and the length of the majority of the duplexes ranged between 6 and 8 bps. We were curious if other models would generate similar results and whether adding longer duplexes of 17 bps would affect the conclusions. We developed a gradient-descent fitting program for obtaining free-energy parameters—the changes in Gibbs free energy (ΔG), enthalpy (ΔH), and entropy (ΔS), and the melting temperature (Tm)—directly from the experimental melting curves. Using gradient descent and a genetic algorithm, the duplex melting results were combined with the standard benchmark data to obtain bp parameters. Both the standard (Turner) model and a new model that includes length-dependent terms were tested. Both models could fit the standard benchmark data; however, the new model could handle longer sequences better. We developed an updated strategy for fitting the duplex melting data.

Theoretical Investigation of Thermal Expansion Coefficients of SiC Reinforced Copper Matrix Composites

The thermal expansion coefficient (CTE) of the copper element, which is widely used in the electronics industry, is quite high. It is of great importance to decrease the CTE value in order not to deform against the heat it is exposed to. In this study, it is aimed to theoretically examine the changes in CTE value when SiC supplement is applied to pure copper. For this purpose, CTE value calculations were made according to Kerner and Turner's models for composites that were reinforced at different rates by volume. Sample studies in the literature have been utilized for percent component ratios. In this context, the amount of reinforcement was adjusted to be 5, 10, 15, and 20vol.% by volume. According to the findings, it was observed that there was ̴ %4-17 decrease in CTE value based on the Kerner model and ̴ %7-26 decrease based on the Turner model.

Prospects for recurrent neural network models to learn RNA biophysics from high-throughput data

RNA is a functionally versatile molecule that plays key roles in genetic regulation and in emerging technologies to control biological processes. Computational models of RNA secondary structure are well-developed but often fall short in making quantitative predictions of the behavior of multi-RNA complexes. Recently, large datasets characterizing hundreds of thousands of individual RNA complexes have emerged as rich sources of information about RNA energetics. Meanwhile, advances in machine learning have enabled the training of complex neural networks from large datasets. Here, we assess whether a recurrent neural network model, Ribonet, can learn from high-throughput binding data, using simulation and experimental studies to test model accuracy but also determine if they learned meaningful information about the biophysics of RNA folding. We began by evaluating the model on energetic values predicted by the Turner model to assess whether the neural network could learn a representation that recovered known biophysical principles. First, we trained Ribonet to predict the simulated free energy of an RNA in complex with multiple input RNAs. Our model accurately predicts free energies of new sequences but also shows evidence of having learned base pairing information, as assessed by in silico double mutant analysis. Next, we extended this model to predict the simulated affinity between an arbitrary RNA sequence and a reporter RNA. While these more indirect measurements precluded the learning of basic principles of RNA biophysics, the resulting model achieved sub-kcal/mol accuracy and enabled design of simple RNA input responsive riboswitches with high activation ratios predicted by the Turner model from which the training data were generated. Finally, we compiled and trained on an experimental dataset comprising over 600,000 experimental affinity measurements published on the Eterna open laboratory. Though our tests revealed that the model likely did not learn a physically realistic representation of RNA interactions, it nevertheless achieved good performance of 0.76 kcal/mol on test sets with the application of transfer learning and novel sequence-specific data augmentation strategies. These results suggest that recurrent neural network architectures, despite being naïve to the physics of RNA folding, have the potential to capture complex biophysical information. However, more diverse datasets, ideally involving more direct free energy measurements, may be necessary to train de novo predictive models that are consistent with the fundamentals of RNA biophysics.Author SummaryThe precise design of RNA interactions is essential to gaining greater control over RNA-based biotechnology tools, including designer riboswitches and CRISPR-Cas9 gene editing. However, the classic model for energetics governing these interactions fails to quantitatively predict the behavior of RNA molecules. We developed a recurrent neural network model, Ribonet, to quantitatively predict these values from sequence alone. Using simulated data, we show that this model is able to learn simple base pairing rules, despite having no a priori knowledge about RNA folding encoded in the network architecture. This model also enables design of new switching RNAs that are predicted to be effective by the “ground truth” simulated model. We applied transfer learning to retrain Ribonet using hundreds of thousands of RNA-RNA affinity measurements and demonstrate simple data augmentation techniques that improve model performance. At the same time, data diversity currently available set limits on Ribonet’s accuracy. Recurrent neural networks are a promising tool for modeling nucleic acid biophysics and may enable design of complex RNAs for novel applications.