Biology subjects

Uckelmann, M.

Publications and source records attributed to Uckelmann, M..

4 recordsLinked to original sources

bioRxiv2026

LPT: Orchestrating bounded agentic loops for automated protein binder design

Current large language models (LLMs) can reason over scientific information and use code-based tools, but their training knowledge is broad rather than specialized, can be out of date and is hard to attribute to sources. Furthermore, unconstrained agentic workflows and unlimited tool use can consume large amounts of tokens. Here we present LPT (little protein tiger), a framework for fixed orchestration of LLM stages, each running a bounded agentic loop with custom system prompts and tool access, to enable de novo protein binder design from a single natural language prompt. The LLM stages can query a curated literature database, containing ~14000 papers digested into key findings, enabling recall of specialized information. An LLM with database access answered 41/48 test questions drawn from database key findings correctly, while a model without access answered none. In three end-to-end design campaigns, initiated from a single prompt, LPT autonomously identified the design intent, selected targets, structures and hotspot residues and designed candidate binders to disrupt CALCRL/RAMP1, PD-1/PD-L1 and PVR-TIGIT interactions. Cross-validation with multiple folding models confirms a high in silico success rate at minimal token consumption and low computational costs.

bioinformatics↗

bioRxiv2025

Integrating computational protein structure predictions and genetic dependencies yields an atlas of human multi-protein complexes (AHMPC)

Knowledge of which proteins interact to form functional complexes in cells is essential for understanding molecular mechanisms in biology. Structure prediction methods recently allowed to compute the Human Interactome of likely binary protein interactions. We combine computational predictions with orthogonal functional data from the Dependency Map that estimate the correlation between genetic dependencies and vulnerabilities of the corresponding gene pairs. This revealed groups of proteins that likely form larger complexes. Clustering analysis followed by AlphaFold3 multi-protein complex predictions and AlphaBridge analysis provided the basis to construct and atlas of human multi-protein complexes (AHMPC), currently encompassing 354 high-confidence predicted multi-protein complexes. These include well-known assemblies and new ones - such as a complex involving SYS1, JTB, and ARFRP1 that we validate experimentally, suggesting an unexpected role of JTB in Golgi traficking. To enable the research community to explore the AHMPC and enable further discovery, we cluster all complexes using functional and disease-related embeddings, demonstrate how structured prompts allow validation by large language models (LLMs), and make all structures and analysis available online as an open resource at https://ahmpc.eu/.

biochemistry↗

bioRxiv2023

Histone H3.3 lysine 9 and 27 control repressive chromatin states at cryptic cis-regulatory elements and bivalent promoters in mouse embryonic stem cells

Histone modifications are associated with distinct transcriptional states, but it is unclear whether they instruct gene expression. To investigate this, we mutated histone H3.3 K9 and K27 residues in mouse embryonic stem cells (mESCs). Here, we find that H3.3K9 is essential for controlling specific distal intergenic regions and for proper H3K27me3 deposition at promoters. The H3.3K9A mutation resulted in decreased H3K9me3 at regions encompassing endogenous retroviruses and induced a gain of H3K27ac and nascent transcription. These changes in the chromatin environment unleashed cryptic enhancers, resulting in the activation of distinctive transcriptional programs and culminating in protein expression normally restricted to specialized immune cell types. The H3.3K27A mutant disrupted deposition and spreading of the repressive H3K27me3 mark, particularly impacting bivalent genes with higher basal level of H3.3 at promoters. Therefore, H3.3K9 and K27 crucially orchestrate repressive chromatin states at cis-regulatory elements and bivalent promoters, respectively, and instruct proper transcription in mESCs.

genomics↗

bioRxiv2023

Dynamic PRC1-CBX8 stabilizes a porous structure of chromatin condensates

The compaction of chromatin is a prevalent paradigm in gene repression. Chromatin compaction is commonly thought to repress transcription by restricting chromatin accessibility. However, the spatial organisation and dynamics of chromatin compacted by gene-repressing factors are unknown. Using cryo-electron tomography, we solved the three-dimensional structure of chromatin condensed by the Polycomb Repressive Complex 1 (PRC1) in a complex with CBX8. PRC1-condensed chromatin is porous and stabilised through multivalent dynamic interactions of PRC1 with chromatin. Mechanistically, positively charged residues on the internally disordered regions (IDRs) of CBX8 mask negative charges on the DNA to stabilize the condensed state of chromatin. Within condensates, PRC1 remains dynamic while maintaining a static chromatin structure. In differentiated mouse embryonic stem cells, CBX8-bound chromatin remains accessible. These findings challenge the idea of rigidly compacted polycomb domains and instead provides a mechanistic framework for dynamic and accessible PRC1-chromatin condensates.

biophysics↗