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Register a new userMachine Learning Harnesses Molecular Dynamics to Discover New $mu$ Opioid Chemotypes
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Computational chemists typically assay drug candidates by virtually screening compounds against crystal structures of a protein despite the fact that some targets, like the $mu$ Opioid Receptor and other members of the GPCR family, traverse many non-crystallographic states. We discover new conformational states of $mu OR$ with molecular dynamics simulation and then machine learn ligand-structure relationships to predict opioid ligand function. These artificial intelligence models identified a novel $mu$ opioid chemotype.
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Many important analgesics relieve pain by binding to the $mu$-Opioid Receptor ($mu$OR), which makes the $mu$OR among the most clinically relevant proteins of the G Protein Coupled Receptor (GPCR) family. Despite previous studies on the activation pathways of the GPCRs, the mechanism of opiate binding and the selectivity of $mu$OR are largely unknown. We performed extensive molecular dynamics (MD) simulation and analysis to find the selective allosteric binding sites of the $mu$OR and the path opiates take to bind to the orthosteric site. In this study, we predicted that the allosteric site is responsible for the attraction and selection of opiates. Using Markov state models and machine learning, we traced the pathway of opiates in binding to the orthosteric site, the main binding pocket. Our results have important implications in designing novel analgesics.
The goal of the present study is to identify autism using machine learning techniques and resting-state brain imaging data, leveraging the temporal variability of the functional connections (FC) as the only information. We estimated and compared the FC variability across brain regions between typical, healthy subjects and autistic population by analyzing brain imaging data from a world-wide multi-site database known as ABIDE (Autism Brain Imaging Data Exchange). Our analysis revealed that patients diagnosed with autism spectrum disorder (ASD) show increased FC variability in several brain regions that are associated with low FC variability in the typical brain. We then used the enhanced FC variability of brain regions as features for training machine learning models for ASD classification and achieved 65% accuracy in identification of ASD versus control subjects within the dataset. We also used node strength estimated from number of functional connections per node averaged over the whole scan as features for ASD classification.The results reveal that the dynamic FC measures outperform or are comparable with the static FC measures in predicting ASD.
Our main motivation is to propose an efficient approach to generate novel multi-element stable chemical compounds that can be used in real world applications. This task can be formulated as a combinatorial problem, and it takes many hours of human experts to construct, and to evaluate new data. Unsupervised learning methods such as Generative Adversarial Networks (GANs) can be efficiently used to produce new data. Cross-domain Generative Adversarial Networks were reported to achieve exciting results in image processing applications. However, in the domain of materials science, there is a need to synthesize data with higher order complexity compared to observed samples, and the state-of-the-art cross-domain GANs can not be adapted directly. In this contribution, we propose a novel GAN called CrystalGAN which generates new chemically stable crystallographic structures with increased domain complexity. We introduce an original architecture, we provide the corresponding loss functions, and we show that the CrystalGAN generates very reasonable data. We illustrate the efficiency of the proposed method on a real original problem of novel hydrides discovery that can be further used in development of hydrogen storage materials.
RNA function crucially depends on its structure. Thermodynamic models currently used for secondary structure prediction rely on computing the partition function of folding ensembles, and can thus estimate minimum free-energy structures and ensemble populations. These models sometimes fail in identifying native structures unless complemented by auxiliary experimental data. Here, we build a set of models that combine thermodynamic parameters, chemical probing data (DMS, SHAPE), and co-evolutionary data (Direct Coupling Analysis, DCA) through a network that outputs perturbations to the ensemble free energy. Perturbations are trained to increase the ensemble populations of a representative set of known native RNA structures. In the chemical probing nodes of the network, a convolutional window combines neighboring reactivities, enlightening their structural information content and the contribution of local conformational ensembles. Regularization is used to limit overfitting and improve transferability. The most transferable model is selected through a cross-validation strategy that estimates the performance of models on systems on which they are not trained. With the selected model we obtain increased ensemble populations for native structures and more accurate predictions in an independent validation set. The flexibility of the approach allows the model to be easily retrained and adapted to incorporate arbitrary experimental information.
Interaction with divalent cations is of paramount importance for RNA structural stability and function. We here report a detailed molecular dynamics study of all the possible binding sites for Mg$^{2+}$ on a RNA duplex, including both direct (inner sphere) and indirect (outer sphere) binding. In order to tackle sampling issues, we develop a modified version of bias-exchange metadynamics which allows us to simultaneously compute affinities with previously unreported statistical accuracy. Results correctly reproduce trends observed in crystallographic databases. Based on this, we simulate a carefully chosen set of models that allows us to quantify the effects of competition with monovalent cations, RNA flexibility, and RNA hybridization. Our simulations reproduce the decrease and increase of Mg$^{2+}$ affinity due to ion competition and hybridization respectively, and predict that RNA flexibility has a site dependent effect. This suggests a non trivial interplay between RNA conformational entropy and divalent cation binding.
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