The Tortured Proteins Department

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We talk about a big travel month (including Stephanie winning the George Sheldrick Award for Structural Science ), federal funding in light of the upcoming turnover of US political representation, pre-prints, and the use of AI with agentic workflows for science and LLMs for writing. News Links: Derek Lowe's Blog: The Assault On Science Funding Continues Senate votes to block rule giving White House more control over research Estimating global article processing charges paid to 14publishers for open access between 2019 and 2025 Preprints/Blogs: Atomic modeling of radiation damage in cryoelectron microscopy datasets Dynamic view of an allosteric intermediate in a positively cooperative dimer Incidental conformational switching in an allosteric enzyme Anthropic Protein Design Prompts The Rise of Large Language Models and the Direction and Impact of US Federal Research Funding

We chat about a revolving door of consortium meetings for Jaime, follow up on the OMB proposed rule, two mini-protein kinase preprints, and differences between blogs and scholarly work. Preprints/Blogs: De novo design of selective kinase modulators Selective miniprotein inhibitors of Aurora-A kinase designed using interaction-motif scaffolding Ensemble refinement produces consistent R-free values but smaller ensemble sizes than previously reported News Links: Bethesda Declaration one year later The Public Rejects OMB's Federal Financial Assistance Rule

We chat about the conformational ensembles conference, NIH-proposed policy changes, 4!! preprints, & running. NIH news: OMB Proposal Blog Post Summary on OMB Proposal RFI to Cap the Number of Simultaneous Research Project Grants Early Independence Award Preprints: Detection of residual native state entropy changes upon mutation in Fyn SH3 Protein-ligand binding kinetics are primarily controlled by the protein, not the ligand ESMFold2 sampleworks: A Modular Platform for Experimentally Guided Biomolecular Ensemble Generation

NIH Strategic Plan Comments (Due 5/26) Preprint: Cooling fast and slow: Characterising the effects of vitrification in cryo-EM and the subsequent recovery of equilibrium populations cryoAgent: An agentic workflow for robust and adaptive end-to-end cryo-EM image processing You need to make AI guidelines for your lab We’re Training Scientists for a World That No Longer Exists

diffUSE Project April Fools Blog NIH News: Funding Curve Drug Monkey 2025 Grant Report How the 2025 NIH grant terminations varied by researchers’ demographic groups Preprints: Intrinsic dataset features drive mutational effect prediction by protein language models Ribosome Molecular Aging Shapes Translation Dynamics AI Grad Student: Why I may ‘hire’ AI instead of a graduate student Vibe physics: The AI grad student

Topics: Olympics NIH Bureaucracy - Grants & Leaderships Preprints 12 episodes of TTPD! Claude Code & Slack Apps San Francisco Half Preprints: Bidirectional allosteric ligand regulation in a central glycolytic enzyme Large-scale exploration of protein space by automated NMR

Preprints: Improving Cryo-EM Optimization Robustness with an Optimal Transport Loss Function for Noisy Images Protein folding success depends on the direction and speed of polypeptide chain appearance Jeremy Reiter 's gene list

Year in Review & 2026 Predictions Preprints: Rewriting protein alphabets with language models Fine-tuning protein language models on human spatial constraint yields state-of-the-art variant effect prediction Prachee Avasthi Blog Post: How to Not Make a Scientific Journal by Accident

Topics: Government Shutdown/Reopening Travels The impact of Jane Richardson AI Peer Review tools Preprint 1: Hit or Miss: Understanding Emergence and Absence of Homo-oligomeric Contacts in Protein Language Models The Drain of Scientific Publishing Big experiments are only big if they can fail

Topics: Compact for Academic Excellence in Higher Education Government Shutdown HHMI's new open science policies Shrinking PhD pools The Nobel Prizes The Bear TLOS Reactions Preprint: Experiment-guided AlphaFold3 resolves accurate protein ensembles

Latest News: -H1B changes & chaos -Who determines what gets into Pubmed (Literature Selection Technical Review Committee) Preprints: Generative design of novel bacteriophages with genome language models Improved cryo-EM reconstruction of sub-50 kDa complexes using 2D template matching High-resolution ab initio reconstruction enables cryo-EM structure determination of small particles (See great biorxiv comment on the paper!)

We chatted about the recent meetings, latest news, open science, social media, and, of course, the recent engagement. Preprints: Aromatic Ring Flips Reveal Reshaping of Protein Dynamics in Crystals and Complexes Computational design of conformation-biasing mutations to alter protein functions Why do we still publish in scientific journals? - Pedro Beltrao's blog The diffUSE Project OpenADMET

We chatted about the latest news, including the new NIH open access policy, trends observed with scientists using LLMs, & the Montpelier Mile race. "The new Administration began weaponizing what should not be weaponized - the health of all Americans...creating chaos and promoting an...unreasoned agenda of blacklisting certain topics, that...has absolutely nothing to do with the promotion of science." - Judge William Young (reported by Max Kozlov, Nature News) An Evaluation of Biomolecular Energetics Learned by AlphaFold Product-stabilized filamentation by human glutamine synthetase allosterically tunes metabolic activity

- News round-up - Conformational Ensembles Conference - Preprints discussed: Multiscale guidance of AlphaFold3 with heterogeneous cryo-EM data (https://www.arxiv.org/abs/2506.04490) Boltz-2 Towards Accurate and EfficientBinding Affinity Prediction (https://jeremywohlwend.com/assets/boltz2.pdf) - Guiding vibe coding for science -Dipsea & Montpelier Mile

The preprints discussed in this episode. Structures of protein folding intermediates on the ribosome: https://www.biorxiv.org/content/10.1101/2025.04.07.647236v1.full.pdf AF2χ: Predicting protein side-chain rotamer distributions with AlphaFold2: https://www.biorxiv.org/content/10.1101/2025.04.16.649219v1.full.pdf

We chatted about the continued chaos of science infrastructure and dived into some cool science from recent meetings Jaime and Stephanie attended. We introduce two new segments: preprints and how to do science. The pre-prints discussed in this episode: Counting particles could give wrong probabilities in Cryo-Electron Microscopy- https://www.biorxiv.org/content/10.1101/2025.03.27.644168v1 Enthalpy-entropy trade-offs in the evolution of ligand specificity in a superfamily of transcription factors- https://www.biorxiv.org/content/10.1101/2025.03.23.644840v1?rss=1 Conserved energetic changes drive function in an ancient protein fold- https://www.biorxiv.org/content/10.1101/2025.04.02.646877v1

Episode 1. We discuss the declining support of science in the US and how it may impact the future of graduate science education. Recorded- 3/14/2025