Meta-Learning Enables Complex Cluster-Specific Few-Shot Binding Affinity Prediction for Protein-Protein Interactions.

Predicting protein-protein interaction (PPI) binding affinities in unseen protein complex clusters is essential for elucidating complex protein interactions and for the targeted screening of peptide- or protein-based drugs. We introduce MCGLPPI++, a meta-learning framework designed to improve the adaptability of pretrained geometric models in such scenarios. To effectively boost the meta-learning optimization by injecting prior intersample distribution knowledge, three specially designed training sample cluster splitting patterns based on protein interaction interfaces are introduced.

Expert-guided protein language models enable accurate and blazingly fast fitness prediction.

Motivation: Exhaustive experimental annotation of the effect of all known protein variants remains daunting and expensive, stressing the need for scalable effect predictions. We introduce VespaG, a blazingly fast missense amino acid variant effect predictor, leveraging protein language model (pLM) embeddings as input to a minimal deep learning model.

Results: To overcome the sparsity of experimental training data, we created a dataset of 39 million single amino acid variants from the human proteome applying the multiple sequence alignment-based effect predictor GEMME as a pseudo standard-of-truth.

Critical assessment of missense variant effect predictors on disease-relevant variant data.

Regular, systematic, and independent assessment of computational tools used to predict the pathogenicity of missense variants is necessary to evaluate their clinical and research utility and suggest directions for future improvement. Here, as part of the sixth edition of the Critical Assessment of Genome Interpretation (CAGI) challenge, we assess missense variant effect predictors (or variant impact predictors) on an evaluation dataset of rare missense variants from disease-relevant databases. Our assessment evaluates predictors submitted to the CAGI6 Annotate-All-Missense challenge, predictors commonly used by the clinical genetics community, and recently developed deep learning methods for variant effect prediction.

Protein embeddings predict binding residues in disordered regions.

The identification of protein binding residues helps to understand their biological processes as protein function is often defined through ligand binding, such as to other proteins, small molecules, ions, or nucleotides. Methods predicting binding residues often err for intrinsically disordered proteins or regions (IDPs/IDPRs), often also referred to as molecular recognition features (MoRFs). Here, we presented a novel machine learning (ML) model trained to specifically predict binding regions in IDPRs.

Alignment-based Protein Mutational Landscape Prediction: Doing More with Less.

The wealth of genomic data has boosted the development of computational methods predicting the phenotypic outcomes of missense variants. The most accurate ones exploit multiple sequence alignments, which can be costly to generate. Recent efforts for democratizing protein structure prediction have overcome this bottleneck by leveraging the fast homology search of MMseqs2.

LambdaPP: Fast and accessible protein-specific phenotype predictions.

The availability of accurate and fast artificial intelligence (AI) solutions predicting aspects of proteins are revolutionizing experimental and computational molecular biology. The webserver LambdaPP aspires to supersede PredictProtein, the first internet server making AI protein predictions available in 1992. Given a protein sequence as input, LambdaPP provides easily accessible visualizations of protein 3D structure, along with predictions at the protein level (GeneOntology, subcellular location), and the residue level (binding to metal ions, small molecules, and nucleotides; conservation; intrinsic disorder; secondary structure; alpha-helical and beta-barrel transmembrane segments; signal-peptides; variant effect) in seconds.

Embeddings from protein language models predict conservation and variant effects.

The emergence of SARS-CoV-2 variants stressed the demand for tools allowing to interpret the effect of single amino acid variants (SAVs) on protein function. While Deep Mutational Scanning (DMS) sets continue to expand our understanding of the mutational landscape of single proteins, the results continue to challenge analyses. Protein Language Models (pLMs) use the latest deep learning (DL) algorithms to leverage growing databases of protein sequences.