lociPARSE: A Locality-aware Invariant Point Attention Model for Scoring RNA 3D Structures.

A scoring function that can reliably assess the accuracy of a 3D RNA structural model in the absence of experimental structure is not only important for model evaluation and selection but also useful for scoring-guided conformational sampling. However, high-fidelity RNA scoring has proven to be difficult using conventional knowledge-based statistical potentials and currently available machine learning-based approaches. Here, we present lociPARSE, a locality-aware invariant point attention architecture for scoring RNA 3D structures.

Sifting through the noise: A survey of diffusion probabilistic models and their applications to biomolecules.

Diffusion probabilistic models have made their way into a number of high-profile applications since their inception. In particular, there has been a wave of research into using diffusion models in the prediction and design of biomolecular structures and sequences. Their growing ubiquity makes it imperative for researchers in these fields to understand them.

Single-sequence protein-RNA complex structure prediction by geometric attention-enabled pairing of biological language models.

Ground-breaking progress has been made in structure prediction of biomolecular assemblies, including the recent breakthrough of AlphaFold 3. However, it remains challenging for AlphaFold 3 and other state-of-the-art deep learning-based methods to accurately predict protein-RNA complex structures, in part due to the limited availability of evolutionary and structural information related to protein-RNA interactions that are used as inputs to the existing approaches. Here, we introduce ProRNA3D-single, a new deep-learning framework for protein-RNA complex structure prediction with only single-sequence input.

The landscape of RNA 3D structure modeling with transformer networks.

Transformers are a powerful subclass of neural networks catalyzing the development of a growing number of computational methods for RNA structure modeling. Here, we conduct an objective and empirical study of the predictive modeling accuracy of the emerging transformer-based methods for RNA structure prediction. Our study reveals multi-faceted complementarity between the methods and underscores some key aspects that affect the prediction accuracy.

EquiPNAS: improved protein-nucleic acid binding site prediction using protein-language-model-informed equivariant deep graph neural networks.

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.

lociPARSE: a locality-aware invariant point attention model for scoring RNA 3D structures.

A scoring function that can reliably assess the accuracy of a 3D RNA structural model in the absence of experimental structure is not only important for model evaluation and selection but also useful for scoring-guided conformational sampling. However, high-fidelity RNA scoring has proven to be difficult using conventional knowledge-based statistical potentials and currently-available machine learning-based approaches. Here we present lociPARSE, a locality-aware invariant point attention architecture for scoring RNA 3D structures.

EquiPNAS: improved protein-nucleic acid binding site prediction using protein-language-model-informed equivariant deep graph neural networks.

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.

E(3) equivariant graph neural networks for robust and accurate protein-protein interaction site prediction.

Artificial intelligence-powered protein structure prediction methods have led to a paradigm-shift in computational structural biology, yet contemporary approaches for predicting the interfacial residues (i.e., sites) of protein-protein interaction (PPI) still rely on experimental structures.

The transformative power of transformers in protein structure prediction.

Transformer neural networks have revolutionized structural biology with the ability to predict protein structures at unprecedented high accuracy. Here, we report the predictive modeling performance of the state-of-the-art protein structure prediction methods built on transformers for 69 protein targets from the recently concluded 15th Critical Assessment of Structure Prediction (CASP15) challenge. Our study shows the power of transformers in protein structure modeling and highlights future areas of improvement.

iQDeep: an integrated web server for protein scoring using multiscale deep learning models.

The remarkable recent advances in protein structure prediction have enabled computational modeling of protein structures with considerably higher accuracy than ever before. While state-of-the-art structure prediction methods provide self-assessment confidence scores of their own predictions, an independent and open-access system for protein scoring is still needed that can be applied to a broad range of predictive modeling scenarios. Here, we present iQDeep, an integrated and highly customizable web server for protein scoring, freely available at http://fusion.

PIQLE: protein-protein interface quality estimation by deep graph learning of multimeric interaction geometries.

Motivation: 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.

Results: Here, we present PIQLE, a deep graph learning method for protein-protein interface quality estimation.

Contact-Assisted Threading in Low-Homology Protein Modeling.

The ability to successfully predict the three-dimensional structure of a protein from its amino acid sequence has made considerable progress in the recent past. The progress is propelled by the improved accuracy of deep learning-based inter-residue contact map predictors coupled with the rising growth of protein sequence databases. Contact map encodes interatomic interaction information that can be exploited for highly accurate prediction of protein structures via contact map threading even for the query proteins that are not amenable to direct homology modeling.

PIQLE: protein-protein interface quality estimation by deep graph learning of multimeric interaction geometries.

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.

rrQNet: Protein contact map quality estimation by deep evolutionary reconciliation.

Protein contact maps have proven to be a valuable tool in the deep learning revolution of protein structure prediction, ushering in the recent breakthrough by AlphaFold2. However, self-assessment of the quality of predicted structures are typically performed at the granularity of three-dimensional coordinates as opposed to directly exploiting the rotation- and translation-invariant two-dimensional (2D) contact maps. Here, we present rrQNet, a deep learning method for self-assessment in 2D by contact map quality estimation.

DisCovER: distance- and orientation-based covariational threading for weakly homologous proteins.

Threading a query protein sequence onto a library of weakly homologous structural templates remains challenging, even when sequence-based predicted contact or distance information is used. Contact-assisted or distance-assisted threading methods utilize only the spatial proximity of the interacting residue pairs for template selection and alignment, ignoring their orientation. Moreover, existing threading methods fail to consider the neighborhood effect induced by the query-template alignment.

Recent Advances in Protein Homology Detection Propelled by Inter-Residue Interaction Map Threading.

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.

DeepRefiner: high-accuracy protein structure refinement by deep network calibration.

The DeepRefiner webserver, freely available at http://watson.cse.eng.

Hybridized distance- and contact-based hierarchical structure modeling for folding soluble and membrane proteins.

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.

PolyFold: An interactive visual simulator for distance-based protein folding.

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.

QDeep: distance-based protein model quality estimation by residue-level ensemble error classifications using stacked deep residual neural networks.

Motivation: Protein model quality estimation, in many ways, informs protein structure prediction. Despite their tight coupling, existing model quality estimation methods do not leverage inter-residue distance information or the latest technological breakthrough in deep learning that has recently revolutionized protein structure prediction.

Results: We present a new distance-based single-model quality estimation method called QDeep by harnessing the power of stacked deep residual neural networks (ResNets).

Evaluating the significance of contact maps in low-homology protein modeling using contact-assisted threading.

The development of improved threading algorithms for remote homology modeling is a critical step forward in template-based protein structure prediction. We have recently demonstrated the utility of contact information to boost protein threading by developing a new contact-assisted threading method. However, the nature and extent to which the quality of a predicted contact map impacts the performance of contact-assisted threading remains elusive.

SPECS: Integration of side-chain orientation and global distance-based measures for improved evaluation of protein structural models.

Significant advancements in the field of protein structure prediction have necessitated the need for objective and robust evaluation of protein structural models by comparing predicted models against the experimentally determined native structures to quantitate their structural similarities. Existing protein model versus native similarity metrics either consider the distances between alpha carbon (Cα) or side-chain atoms for computing the similarity. However, side-chain orientation of a protein plays a critical role in defining its conformation at the atomic-level.

Does inclusion of residue-residue contact information boost protein threading?

Template-based modeling is considered as one of the most successful approaches for protein structure prediction. However, reliably and accurately selecting optimal template proteins from a library of known protein structures having similar folds as the target protein and making correct alignments between the target sequence and the template structures, a template-based modeling technique known as threading, remains challenging, particularly for non- or distantly-homologous protein targets. With the recent advancement in protein residue-residue contact map prediction powered by sequence co-evolution and machine learning, here we systematically analyze the effect of inclusion of residue-residue contact information in improving the accuracy and reliability of protein threading.

refineD: improved protein structure refinement using machine learning based restrained relaxation.

Motivation: Protein structure refinement aims to bring moderately accurate template-based protein models closer to the native state through conformational sampling. However, guiding the sampling towards the native state by effectively using restraints remains a major issue in structure refinement.

Results: Here, we develop a machine learning based restrained relaxation protocol that uses deep discriminative learning based binary classifiers to predict multi-resolution probabilistic restraints from the starting structure and subsequently converts these restraints to be integrated into Rosetta all-atom energy function as additional scoring terms during structure refinement.

An analysis and evaluation of the WeFold collaborative for protein structure prediction and its pipelines in CASP11 and CASP12.

Every two years groups worldwide participate in the Critical Assessment of Protein Structure Prediction (CASP) experiment to blindly test the strengths and weaknesses of their computational methods. CASP has significantly advanced the field but many hurdles still remain, which may require new ideas and collaborations. In 2012 a web-based effort called WeFold, was initiated to promote collaboration within the CASP community and attract researchers from other fields to contribute new ideas to CASP.