Paper List
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Macroscopic Dominance from Microscopic Extremes: Symmetry Breaking in Spatial Competition
This paper addresses the fundamental question of how microscopic stochastic advantages in spatial exploration translate into macroscopic resource domi...
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Linear Readout of Neural Manifolds with Continuous Variables
This paper addresses the core challenge of quantifying how the geometric structure of high-dimensional neural population activity (neural manifolds) d...
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Theory of Cell Body Lensing and Phototaxis Sign Reversal in “Eyeless” Mutants of Chlamydomonas
This paper solves the core puzzle of how eyeless mutants of Chlamydomonas exhibit reversed phototaxis by quantitatively modeling the competition betwe...
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Cross-Species Transfer Learning for Electrophysiology-to-Transcriptomics Mapping in Cortical GABAergic Interneurons
This paper addresses the challenge of predicting transcriptomic identity from electrophysiological recordings in human cortical interneurons, where li...
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Uncovering statistical structure in large-scale neural activity with Restricted Boltzmann Machines
This paper addresses the core challenge of modeling large-scale neural population activity (1500-2000 neurons) with interpretable higher-order interac...
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Realizing Common Random Numbers: Event-Keyed Hashing for Causally Valid Stochastic Models
This paper addresses the critical problem that standard stateful PRNG implementations in agent-based models violate causal validity by making random d...
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A Standardized Framework for Evaluating Gene Expression Generative Models
This paper addresses the critical lack of standardized evaluation protocols for single-cell gene expression generative models, where inconsistent metr...
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Single Molecule Localization Microscopy Challenge: A Biologically Inspired Benchmark for Long-Sequence Modeling
This paper addresses the core challenge of evaluating state-space models on biologically realistic, sparse, and stochastic temporal processes, which a...
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.