arXiv subjects

Sjors H. W. Scheres

Publications and source records attributed to Sjors H. W. Scheres.

5 recordsLinked to original sources

arXiv2026

The microscope is the mask: privileged views and labels from a cryo-ET forward model

We explore the use of simulated data for training a model for protein annotation in crowded cryo-electron tomography volumes reconstructed from images collected at limited tilt angles and severely corrupted by the measurement operator. Firstly, we leverage the corruptions imposed by the forward model to generate domain-specific augmented paired views of the exact same scene for an invariance objective integrated into the LeJEPA self-supervised training framework. Secondly, we use additional information from the simulation pipeline such as the positions and identity of proteins in the simulated volumes to inform the architecture of the model and the loss function, so that semantic information is localised at protein positions in the resulting dense feature volume. The resulting model, CARNIVAL, is evaluated without finetuning on classification and detection tasks in real tomograms, using a benchmark dataset containing multiple protein types and two tomogram processing types. We show that CARNIVAL outperforms a state-of-the-art model trained using a contrastive objective on simulated data but without forward model-based paired views or privileged information.

cs.CV↗

arXiv2026

DBMol: Design of High-Affinity, Target-Specific Small Molecules through Structure Prediction Models

Designing small molecule ligands that bind with high affinity to specific protein pockets is a fundamental goal in drug discovery, as small molecules constitute a major fraction of approved therapeutics. Recent breakthroughs in structure prediction, such as AlphaFold-3 and Boltz-2, enable accurate biomolecular interaction prediction and show promise as foundation models for downstream tasks, including binding affinity prediction. We propose to leverage these models and introduce DBMol, a new structure predictor-guided framework for de novo small molecule design. DBMol formulates an alternating optimization and projection process. In the optimization stage, DBMol starts from an initial molecule and uses gradient-based optimization to improve pocket-specific interactions and predicted binding affinity using a structure prediction model. In the projection stage, a flow-matching model maps the optimized molecular graph to discrete and chemically valid molecules. Experiments show that DBMol effectively optimizes the Boltz-2 affinity proxy and generates molecules with strong predicted affinity and specificity under Boltz-2 evaluation. To reduce self-confirmation bias, we further evaluate generated molecules using held-out metrics, including AF3-based evaluation. DBMol substantially improves pocket coverage while maintaining molecular diversity over unconditional generation, and is competitive under held-out metrics despite the absence of reference-ligand supervision. These results support the promise of structure prediction models as effective optimization signals for de novo molecular design.

cs.LG↗

arXiv2025

All-atom inverse protein folding through discrete flow matching

The recent breakthrough of AlphaFold3 in modeling complex biomolecular interactions, including those between proteins and ligands, nucleotides, or metal ions, creates new opportunities for protein design. In so-called inverse protein folding, the objective is to find a sequence of amino acids that adopts a target protein structure. Many inverse folding methods struggle to predict sequences for complexes that contain non-protein components, and perform poorly with complexes that adopt multiple structural states. To address these challenges, we present ADFLIP (All-atom Discrete FLow matching Inverse Protein folding), a generative model based on discrete flow-matching for designing protein sequences conditioned on all-atom structural contexts. ADFLIP progressively incorporates predicted amino acid side chains as structural context during sequence generation and enables the design of dynamic protein complexes through ensemble sampling across multiple structural states. Furthermore, ADFLIP implements training-free classifier guidance sampling, which allows the incorporation of arbitrary pre-trained models to optimise the designed sequence for desired protein properties. We evaluated the performance of ADFLIP on protein complexes with small-molecule ligands, nucleotides, or metal ions, including dynamic complexes for which structure ensembles were determined by nuclear magnetic resonance (NMR). Our model achieves state-of-the-art performance in single-structure and multi-structure inverse folding tasks, demonstrating excellent potential for all-atom protein design. The code is available at https://github.com/ykiiiiii/ADFLIP.

q-bio.BM↗

arXiv2024

Community recommendations on cryoEM data archiving and validation

In January 2020, a workshop was held at EMBL-EBI (Hinxton, UK) to discuss data requirements for deposition and validation of cryoEM structures, with a focus on single-particle analysis. The meeting was attended by 45 experts in data processing, model building and refinement, validation, and archiving of such structures. This report describes the workshop's motivation and history, the topics discussed, and consensus recommendations resulting from the workshop. Some challenges for future methods-development efforts in this area are also highlighted, as is the implementation to date of some of the recommendations.

q-bio.BM↗

arXiv2023

A Graph Neural Network Approach to Automated Model Building in Cryo-EM Maps

Electron cryo-microscopy (cryo-EM) produces three-dimensional (3D) maps of the electrostatic potential of biological macromolecules, including proteins. Along with knowledge about the imaged molecules, cryo-EM maps allow de novo atomic modelling, which is typically done through a laborious manual process. Taking inspiration from recent advances in machine learning applications to protein structure prediction, we propose a graph neural network (GNN) approach for automated model building of proteins in cryo-EM maps. The GNN acts on a graph with nodes assigned to individual amino acids and edges representing the protein chain. Combining information from the voxel-based cryo-EM data, the amino acid sequence data and prior knowledge about protein geometries, the GNN refines the geometry of the protein chain and classifies the amino acids for each of its nodes. Application to 28 test cases shows that our approach outperforms the state-of-the-art and approximates manual building for cryo-EM maps with resolutions better than 3.5 Å.

q-bio.QM↗