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Guenther, J.

Publications and source records attributed to Guenther, J..

4 recordsLinked to original sources

Which pLM to choose?

AO_SCPLOWBSTRACTC_SCPLOWProtein-language models (pLMs) provide a novel means for mapping the protein space. Which of these new maps best advances specific biological analyses, however, is not obvious. To elucidate the principles of model selection, we benchmarked fourteen pLMs, spanning several orders of magnitude in parameter count, across a hundred million protein pairs, to assess how well they capture sequence, structure, and function similarity. For each model, we distinguish inherent information, i.e. signal recoverable from raw-embedding distances, and extractable information, i.e. signal revealed through additional supervised training. Three key results emerge. First, pLM protein representation space is inherently different from the space of biological protein representations, i.e. sequences or structures. Here, a size-performance paradox is salient - mid-scale foundation models are as good as much larger ones in reflecting all tested biological properties. Second, pLM representations compress and store biological information in proportion to model size. That is, a lightweight feed-forward network can be trained on embedding pairs to predict said biological properties well - a capacity dividend. Finally, we observe that a task-specific learning radically reshapes the embedding space, gaining inherent understanding of the task, but garbling any further extractions. In other words, smaller pLMs can provide efficient and compute-light general insight. Larger models are advantageous only when fine-tuning is planned to accomplish a specific task. Furthermore, representations generated by "specialist" models are not immediately generalizable throughout protein biology. Thus, for pLMs, bigger isnt always better.

bioinformatics↗

CACHE Challenge #1: targeting the WDR domain of LRRK2, a Parkinson's Disease associated protein.

The CACHE challenges are a series of prospective benchmarking exercises meant to evaluate progress in the field of computational hit-finding. Here we report the results of the inaugural CACHE #1 challenge in which 23 computational teams each selected up to 100 commercially available compounds that they predicted would bind to the WDR domain of the Parkinsons disease target LRRK2, a domain with no known ligand and only an apo structure in the PDB. The lack of known binding data and presumably low druggability of the target is a challenge to computational hit finding methods. Seventy-three of the 1955 procured molecules bound LRRK2 in an SPR assay with KD lower than 150 M and were advanced to a hit expansion phase where computational teams each selected up to 50 analogs each. Binding was observed in two orthogonal assays with affinities ranging from 18 to 140 M for seven chemically diverse series. The seven successful computational workflows varied in their screening strategies and techniques. Three used molecular dynamics to produce a conformational ensemble of the targeted site, three included a fragment docking step, three implemented a generative design strategy and five used one or more deep learning steps. CACHE #1 reflects a highly exploratory phase in computational drug design where participants sometimes adopted strikingly diverging screening strategies. Machine-learning accelerated methods achieved similar results to brute force (e.g. exhaustive) docking. First-in-class, experimentally confirmed compounds were rare and weakly potent, indicating that recent advances are not sufficient to effectively address challenging targets.

biochemistry↗

JUMP Cell Painting dataset: morphological impact of 136,000 chemical and genetic perturbations

Image-based profiling has emerged as a powerful technology for various steps in basic biological and pharmaceutical discovery, but the community has lacked a large, public reference set of data from chemical and genetic perturbations. Here we present data generated by the Joint Undertaking for Morphological Profiling (JUMP)-Cell Painting Consortium, a collaboration between 10 pharmaceutical companies, six supporting technology companies, and two non-profit partners. When completed, the dataset will contain images and profiles from the Cell Painting assay for over 116,750 unique compounds, over-expression of 12,602 genes, and knockout of 7,975 genes using CRISPR-Cas9, all in human osteosarcoma cells (U2OS). The dataset is estimated to be 115 TB in size and capturing 1.6 billion cells and their single-cell profiles. File quality control and upload is underway and will be completed over the coming months at the Cell Painting Gallery: https://registry.opendata.aws/cellpainting-gallery. A portal to visualize a subset of the data is available at https://phenaid.ardigen.com/jumpcpexplorer/.

bioinformatics↗

Heterologous expression of PtAAS1 reveals the metabolic potential of the common plant metabolite phenylacetaldehyde for auxin synthesis in planta

Aromatic aldehydes and amines are common plant metabolites involved in several specialized metabolite biosynthesis pathways. Recently, we showed that the aromatic aldehyde synthase PtAAS1 and the aromatic amino acid decarboxylase PtAADC1 contribute to the herbivory-induced formation of volatile 2-phenylethanol and its glucoside 2-phenylethyl-{beta}-D-glucopyranoside in Populus trichocarpa. To gain insights into alternative metabolic fates of phenylacetaldehyde and 2-phenylethylamine beyond alcohol and alcohol glucoside formation, we expressed PtAAS1 and PtAADC1 heterologously in Nicotiana benthamiana and analyzed plant extracts using untargeted LC-qTOF-MS analysis. While the metabolomes of PtAADC1-expressing plants did not significantly differ from those of control plants, expression of PtAAS1 resulted in the accumulation of phenylacetic acid (PAA) and PAA-amino acid conjugates, identified as PAA-aspartate and PAA-glutamate. Moreover, targeted LC-MS/MS analysis showed that PtAAS1-expressing plants accumulated significant amounts of free PAA. The measurement of PAA and PAA-Asp in undamaged and herbivory-damaged poplar leaves revealed significantly induced accumulation of PAA-Asp while levels of free PAA remained unaltered by herbivore treatment. Sequence comparisons and transcriptome analysis showed that members of a small gene family comprising five putative auxin-amido synthetase GH3 genes potentially involved in the conjugation of auxins like PAA with amino acids were significantly upregulated upon herbivory in P. trichocarpa leaves. Overall, our data indicates that phenylacetaldehyde generated by poplar PtAAS1 serves as a hub metabolite linking the biosynthesis of volatile, non-volatile herbivory-induced specialized metabolites, and phytohormones, suggesting that growth and defense are balanced on a metabolic level.

plant biology↗