Paper List
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Discovery of a Hematopoietic Manifold in scGPT Yields a Method for Extracting Performant Algorithms from Biological Foundation Model Internals
This work addresses the core challenge of extracting reusable, interpretable, and high-performance biological algorithms from the opaque internal repr...
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MS2MetGAN: Latent-space adversarial training for metabolite–spectrum matching in MS/MS database search
This paper addresses the critical bottleneck in metabolite identification: the generation of high-quality negative training samples that are structura...
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Toward Robust, Reproducible, and Widely Accessible Intracranial Language Brain-Computer Interfaces: A Comprehensive Review of Neural Mechanisms, Hardware, Algorithms, Evaluation, Clinical Pathways and Future Directions
This review addresses the core challenge of fragmented and heterogeneous evidence that hinders the clinical translation of intracranial language BCIs,...
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Less Is More in Chemotherapy of Breast Cancer
通过纳入细胞周期时滞和竞争项，解决了现有肿瘤-免疫模型的过度简化问题，以定量比较化疗方案。
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Fold-CP: A Context Parallelism Framework for Biomolecular Modeling
This paper addresses the critical bottleneck of GPU memory limitations that restrict AlphaFold 3-like models to processing only a few thousand residue...
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Open Biomedical Knowledge Graphs at Scale: Construction, Federation, and AI Agent Access with Samyama Graph Database
This paper addresses the core pain point of fragmented biomedical data by constructing and federating large-scale, open knowledge graphs to enable sea...
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Predictive Analytics for Foot Ulcers Using Time-Series Temperature and Pressure Data
This paper addresses the critical need for continuous, real-time monitoring of diabetic foot health by developing an unsupervised anomaly detection fr...
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Hypothesis-Based Particle Detection for Accurate Nanoparticle Counting and Digital Diagnostics
This paper addresses the core challenge of achieving accurate, interpretable, and training-free nanoparticle counting in digital diagnostic assays, wh...
Topological Enhancement of Protein Kinetic Stability
BioISI – Instituto de Biossistemas e Ciências Integrativas and Departamento de Física, Faculdade de Ciências, Universidade de Lisboa, 1749-016, Lisboa, Portugal
30秒速读
IN SHORT: This work addresses the long-standing puzzle of why knotted proteins exist by demonstrating that deep knots provide a functional advantage through enhanced kinetic stability, not equilibrium thermodynamics.
核心创新
- Methodology Introduces a controlled computational framework (LTyP vs. non-LTyP Monte Carlo simulations) to isolate the pure topological effect of knots from sequence, structure, and energetic contributions.
- Biology Reveals a strong, asymmetric dependence on knot depth: deep knots (e.g., YibK) suppress unfolding transitions by >1 order of magnitude, dramatically enhancing kinetic stability, while shallow knots have minimal effect.
- Theory Integrates a reverse evolution model, showing that kinetic stabilization is sequence-dependent, emerging fully only with increased amino acid alphabet complexity, providing an evolutionary rationale for knotted protein conservation.
主要结论
- Deep protein knots (e.g., YibK) enhance kinetic stability (resistance to unfolding) by more than an order of magnitude compared to topology-breaking controls, while shallow knots show minimal effect.
- Kinetic stability increases sharply with knot depth, whereas foldability is only moderately affected, revealing an asymmetric topological constraint favoring native state persistence.
- Kinetic stabilization is sequence-dependent: early, low-complexity (10-letter alphabet) sequences exhibit weaker resistance to unfolding, with stabilization becoming pronounced only with modern (20-letter) alphabet complexity.
摘要: Knotted proteins embed a physical (i.e., open) knot within their native structures. For decades, significant effort has been devoted to elucidating the functional role of knots in proteins, yet no consensus has been reached. Here, using extensive Monte Carlo off-lattice simulations of a simple structure-based model, we isolate the effect of topology by comparing simulations that preserve the linear topology of the chain with simulations that allow chain crossings. This controlled framework enables us to isolate topological effects from sequence, structure and energetic contributions. We show that protein kinetic stability, defined as resistance to unfolding at a fixed temperature, is higher in knotted proteins. Additionally, kinetic stability increases significantly with knot depth, whereas foldability (or folding efficiency) is comparatively less affected. By considering a simple model of protein evolution in which amino-acid alphabet size is used as a proxy for evolutionary time, we find that increasing primary-sequence complexity through the addition of biotic amino acids predominantly enhances kinetic stability. Taken together, these results indicate that kinetic stability is a functional advantage conferred by protein knots and suggest that evolutionary pressure for kinetic stability could contribute to the persistence of knotted proteins.