Paper List
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MCP-AI: Protocol-Driven Intelligence Framework for Autonomous Reasoning in Healthcare
This paper addresses the critical gap in healthcare AI systems that lack contextual reasoning, long-term state management, and verifiable workflows by...
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Model Gateway: Model Management Platform for Model-Driven Drug Discovery
This paper addresses the critical bottleneck of fragmented, ad-hoc model management in pharmaceutical research by providing a centralized, scalable ML...
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Tree Thinking in the Genomic Era: Unifying Models Across Cells, Populations, and Species
This paper addresses the fragmentation of tree-based inference methods across biological scales by identifying shared algorithmic principles and stati...
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SSDLabeler: Realistic semi-synthetic data generation for multi-label artifact classification in EEG
This paper addresses the core challenge of training robust multi-label EEG artifact classifiers by overcoming the scarcity and limited diversity of ma...
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Decoding Selective Auditory Attention to Musical Elements in Ecologically Valid Music Listening
This paper addresses the core challenge of objectively quantifying listeners' selective attention to specific musical components (e.g., vocals, drums,...
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Physics-Guided Surrogate Modeling for Machine Learning–Driven DLD Design Optimization
This paper addresses the core bottleneck of translating microfluidic DLD devices from research prototypes to clinical applications by replacing weeks-...
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Mechanistic Interpretability of Antibody Language Models Using SAEs
This work addresses the core challenge of achieving both interpretability and controllable generation in domain-specific protein language models, spec...
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Fluctuating Environments Favor Extreme Dormancy Strategies and Penalize Intermediate Ones
This paper addresses the core challenge of determining how organisms should tune dormancy duration to match the temporal autocorrelation of their envi...
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.