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Protein language models (pLMs) trained on a large corpus of protein sequences have shown unprecedented scalability and broad generalizability in a wide range of predictive modeling tasks, but their power has not yet been harnessed for predicting protein–nucleic acid binding sites, critical for characterizing the interactions between proteins and nucleic acids. Here, we present EquiPNAS, a new pLM-informed E(3) equivariant deep graph neural network framework for improved protein–nucleic acid binding site prediction. By combining the strengths of pLM and symmetry-aware deep graph learning, EquiPNAS consistently outperforms the state-of-the-art methods for both protein–DNA and protein–RNA binding site prediction on multiple datasets across a diverse set of predictive modeling scenarios ranging from using experimental input to AlphaFold2 predictions. Our ablation study reveals that the pLM embeddings used in EquiPNAS are sufficiently powerful to dramatically reduce the dependence on the availability of evolutionary information without compromising on accuracy, and that the symmetry-aware nature of the E(3) equivariant graph-based neural architecture offers remarkable robustness and performance resilience. EquiPNAS is freely available at https://github.com/Bhattacharya-Lab/EquiPNAS.

 

Accurate modeling of protein–protein interaction interface is essential for high-quality protein complex structure prediction. Existing approaches for estimating the quality of a predicted protein complex structural model utilize only the physicochemical properties or energetic contributions of the interacting atoms, ignoring evolutionarily information or inter-atomic multimeric geometries, including interaction distance and orientations.

Here, we present PIQLE, a deep graph learning method for protein–protein interface quality estimation. PIQLE leverages multimeric interaction geometries and evolutionarily information along with sequence- and structure-derived features to estimate the quality of individual interactions between the interfacial residues using a multi-head graph attention network and then probabilistically combines the estimated quality for scoring the overall interface. Experimental results show that PIQLE consistently outperforms existing state-of-the-art methods including DProQA, TRScore, GNN-DOVE and DOVE on multiple independent test datasets across a wide range of evaluation metrics. Our ablation study and comparison with the self-assessment module of AlphaFold-Multimer repurposed for protein complex scoring reveal that the performance gains are connected to the effectiveness of the multi-head graph attention network in leveraging multimeric interaction geometries and evolutionary information along with other sequence- and structure-derived features adopted in PIQLE.

An open-source software implementation of PIQLE is freely available at https://github.com/Bhattacharya-Lab/PIQLE.

Supplementary data are available at Bioinformatics Advances online.

 

Abstract The DeepRefiner webserver, freely available at http://watson.cse.eng.auburn.edu/DeepRefiner/, is an interactive and fully configurable online system for high-accuracy protein structure refinement. Fuelled by deep learning, DeepRefiner offers the ability to leverage cutting-edge deep neural network architectures which can be calibrated for on-demand selection of adventurous or conservative refinement modes targeted at degree or consistency of refinement. The method has been extensively tested in the Critical Assessment of Techniques for Protein Structure Prediction (CASP) experiments under the group name ‘Bhattacharya-Server’ and was officially ranked as the No. 2 refinement server in CASP13 (second only to ‘Seok-server’ and outperforming all other refinement servers) and No. 2 refinement server in CASP14 (second only to ‘FEIG-S’ and outperforming all other refinement servers including ‘Seok-server’). The DeepRefiner web interface offers a number of convenient features, including (i) fully customizable refinement job submission and validation; (ii) automated job status update, tracking, and notifications; (ii) interactive and interpretable web-based results retrieval with quantitative and visual analysis and (iv) extensive help information on job submission and results interpretation via web-based tutorial and help tooltips. 

Sequence-based protein homology detection has emerged as one of the most sensitive and accurate approaches to protein structure prediction. Despite the success, homology detection remains very challenging for weakly homologous proteins with divergent evolutionary profile. Very recently, deep neural network architectures have shown promising progress in mining the coevolutionary signal encoded in multiple sequence alignments, leading to reasonably accurate estimation of inter-residue interaction maps, which serve as a rich source of additional information for improved homology detection. Here, we summarize the latest developments in protein homology detection driven by inter-residue interaction map threading. We highlight the emerging trends in distant-homology protein threading through the alignment of predicted interaction maps at various granularities ranging from binary contact maps to finer-grained distance and orientation maps as well as their combination. We also discuss some of the current limitations and possible future avenues to further enhance the sensitivity of protein homology detection. 

Crystallography and NMR system (CNS) is currently a widely used method for fragment-free ab initio protein folding from inter-residue distance or contact maps. Despite its widespread use in protein structure prediction, CNS is a decade-old macromolecular structure determination system that was originally developed for solving macromolecular geometry from experimental restraints as opposed to predictive modeling driven by interaction map data. As such, the adaptation of the CNS experimental structure determination protocol for ab initio protein folding is intrinsically anomalous that may undermine the folding accuracy of computational protein structure prediction. In this paper, we propose a new CNS-free hierarchical structure modeling method called DConStruct for folding both soluble and membrane proteins driven by distance and contact information. Rigorous experimental validation shows that DConStruct attains much better reconstruction accuracy than CNS when tested with the same input contact map at varying contact thresholds. The hierarchical modeling with iterative self-correction employed in DConStruct scales at a much higher degree of folding accuracy than CNS with the increase in contact thresholds, ultimately approaching near-optimal reconstruction accuracy at higher-thresholded contact maps. The folding accuracy of DConStruct can be further improved by exploiting distance-based hybrid interaction maps at tri-level thresholding, as demonstrated by the better performance of our method in folding free modeling targets from the 12th and 13th rounds of the Critical Assessment of techniques for protein Structure Prediction (CASP) experiments compared to popular CNS- and fragment-based approaches and energy-minimization protocols, some of which even using much finer-grained distance maps than ours. Additional large-scale benchmarking shows that DConStruct can significantly improve the folding accuracy of membrane proteins compared to a CNS-based approach. These results collectively demonstrate the feasibility of greatly improving the accuracy of ab initio protein folding by optimally exploiting the information encoded in inter-residue interaction maps beyond what is possible by CNS. 

Recent advances in distance-based protein folding have led to a paradigm shift in protein structure prediction. Through sufficiently precise estimation of the inter-residue distance matrix for a protein sequence, it is now feasible to predict the correct folds for new proteins much more accurately than ever before. Despite the exciting progress, a dedicated visualization system that can dynamically capture the distance-based folding process is still lacking. Most molecular visualizers typically provide only a static view of a folded protein conformation, but do not capture the folding process. Even among the selected few graphical interfaces that do adopt a dynamic perspective, none of them are distance-based. Here we present PolyFold, an interactive visual simulator for dynamically capturing the distance-based protein folding process through real-time rendering of a distance matrix and its compatible spatial conformation as it folds in an intuitive and easy-to-use interface. PolyFold integrates highly convergent stochastic optimization algorithms with on-demand customizations and interactive manipulations to maximally satisfy the geometric constraints imposed by a distance matrix. PolyFold is capable of simulating the complex process of protein folding even on modest personal computers, thus making it accessible to the general public for fostering citizen science. Open source code of PolyFold is freely available for download at https://github.com/Bhattacharya-Lab/PolyFold . It is implemented in cross-platform Java and binary executables are available for macOS, Linux, and Windows.