Coarse-graining (CG) accelerates molecular simulations of protein dynamics by simulating sets of atoms as singular beads. Backmapping is the opposite operation of bringing lost atomistic details back from the CG representation. While machine learning (ML) has produced accurate and efficient CG simulations of proteins, fast and reliable backmapping remains a challenge. Rule-based methods produce poor all-atom geometries, needing computationally costly refinement through additional simulations. Recently proposed ML approaches outperform traditional baselines but are not transferable between proteins and sometimes generate unphysical atom placements with steric clashes and implausible torsion angles. This work addresses both issues to build a fast, transferable, and reliable generative backmapping tool for CG protein representations. We achieve generalization and reliability through a combined set of innovations: representation based on internal coordinates; an equivariant encoder/prior; a custom loss function that helps ensure local structure, global structure, and physical constraints; and expert curation of high-quality out-of-equilibrium protein data for training. Our results pave the way for out-of-the-box backmapping of coarse-grained simulations for arbitrary proteins.
Soojung Yang, Juno Nam, Johannes C. B. Dietschreit et al.
In molecular dynamics simulations, rare events, such as protein folding, are typically studied using enhanced sampling techniques, most of which are based on the definition of a collective variable (CV) along which acceleration occurs. Obtaining an expressive CV is crucial, but often hindered by the lack of information about the particular event, e.g., the transition from unfolded to folded conformation. We propose a simulation-free data augmentation strategy using physics-inspired metrics to generate geodesic interpolations resembling protein folding transitions, thereby improving sampling efficiency without true transition state samples. This new data can be used to improve the accuracy of classifier-based methods. Alternatively, a regression-based learning scheme for CV models can be adopted by leveraging the interpolation progress parameter.
Recently, deep neural network (DNN)-based drug-target interaction (DTI) models were highlighted for their high accuracy with affordable computational costs. Yet, the models' insufficient generalization remains a challenging problem in the practice of in-silico drug discovery. We propose two key strategies to enhance generalization in the DTI model. The first is to predict the atom-atom pairwise interactions via physics-informed equations parameterized with neural networks and provides the total binding affinity of a protein-ligand complex as their sum. We further improved the model generalization by augmenting a broader range of binding poses and ligands to training data. We validated our model, PIGNet, in the comparative assessment of scoring functions (CASF) 2016, demonstrating the outperforming docking and screening powers than previous methods. Our physics-informing strategy also enables the interpretation of predicted affinities by visualizing the contribution of ligand substructures, providing insights for further ligand optimization.
Prediction models based on deep neural networks are increasingly gaining attention for fast and accurate virtual screening systems. For decision makings in virtual screening, researchers find it useful to interpret an output of classification system as probability, since such interpretation allows them to filter out more desirable compounds. However, probabilistic interpretation cannot be correct for models that hold over-parameterization problems or inappropriate regularizations, leading to unreliable prediction and decision making. In this regard, we concern the reliability of neural prediction models on molecular properties, especially when models are trained with sparse data points and imbalanced distributions. This work aims to propose guidelines for training reliable models, we thus provide methodological details and ablation studies on the following train principles. We investigate the effects of model architectures, regularization methods, and loss functions on the prediction performance and reliability of classification results. Moreover, we evaluate prediction reliability of models on virtual screening scenario. Our result highlights that correct choice of regularization and inference methods is evidently important to achieve high success rate, especially in data imbalanced situation. All experiments were performed under a single unified model implementation to alleviate external randomness in model training and to enable precise comparison of results.