An Interpretable Convolutional Neural Network Framework for Analyzing Molecular Dynamics Trajectories: a Case Study on Functional States for G-Protein-Coupled Receptors.

Molecular dynamics (MD) simulations have made great contribution to revealing structural and functional mechanisms for many biomolecular systems. However, how to identify functional states and important residues from vast conformation space generated by MD remains challenging; thus an intelligent navigation is highly desired. Despite intelligent advantages of deep learning exhibited in analyzing MD trajectory, its black-box nature limits its application. To address this problem, we explore an interpretable convolutional neural network (CNN)-based deep learning framework to automatically identify diverse active states from the MD trajectory for G-protein-coupled receptors (GPCRs), named the ICNNMD model. To avoid the information loss in representing the conformation structure, the pixel representation is introduced, and then the CNN module is constructed to efficiently extract features followed by a fully connected neural network to realize the classification task. More importantly, we design a local interpretable model-agnostic explanation interpreter for the classification result by local approximation with a linear model, through which important residues underlying distinct active states can be quickly identified. Our model showcases higher than 99% classification accuracy for three important GPCR systems with diverse active states. Notably, some important residues in regulating different biased activities are successfully identified, which are beneficial to elucidating diverse activation mechanisms for GPCRs. Our model can also serve as a general tool to analyze MD trajectory for other biomolecular systems. All source codes are freely available at https://github.com/Jane-Liu97/ICNNMD for aiding MD studies.

Correlated RNN Framework to Quickly Generate Molecules with Desired Properties for Energetic Materials in the Low Data Regime.

Motivated by the challenging of deep learning on the low data regime and the urgent demand for intelligent design on highly energetic materials, we explore a correlated deep learning framework, which consists of three recurrent neural networks (RNNs) correlated by the transfer learning strategy, to efficiently generate new energetic molecules with a high detonation velocity in the case of very limited data available. To avoid the dependence on the external big data set, data augmentation by fragment shuffling of 303 energetic compounds is utilized to produce 500,000 molecules to pretrain RNN, through which the model can learn sufficient structure knowledge. Then the pretrained RNN is fine-tuned by focusing on the 303 energetic compounds to generate 7153 molecules similar to the energetic compounds. In order to more reliably screen the molecules with a high detonation velocity, the SMILE enumeration augmentation coupled with the pretrained knowledge is utilized to build an RNN-based prediction model, through which R2 is boosted from 0.4446 to 0.9572. The comparable performance with the transfer learning strategy based on an existing big database (ChEMBL) to produce the energetic molecules and drug-like ones further supports the effectiveness and generality of our strategy in the low data regime. High-precision quantum mechanics calculations further confirm that 35 new molecules present a higher detonation velocity and lower synthetic accessibility than the classic explosive RDX, along with good thermal stability. In particular, three new molecules are comparable to caged CL-20 in the detonation velocity. All the source codes and the data set are freely available at https://github.com/wangchenghuidream/RNNMGM.

Exploring an accurate machine learning model to quickly estimate stability of diverse energetic materials.

High energy and low sensitivity have been the focus of developing new energetic materials (EMs). However, there has been a lack of a quick and accurate method for evaluating the stability of diverse EMs. Here, we develop a machine learning prediction model with high accuracy for bond dissociation energy (BDE) of EMs. A reliable and representative BDE dataset of EMs is constructed by collecting 778 experimental energetic compounds and quantum mechanics calculation. To sufficiently characterize the BDE of EMs, a hybrid feature representation is proposed by coupling the local target bond into the global structure characteristics. To alleviate the limitation of the low dataset, pairwise difference regression is utilized as a data augmentation with the advantage of reducing systematic errors and improving diversity. Benefiting from these improvements, the XGBoost model achieves the best prediction accuracy with R2 of 0.98 and MAE of 8.8 kJ mol-1, significantly outperforming competitive models.