How do we study and model protein folding and misfolding?

Introduction

Protein folding is a critical biological process where a polypeptide chain folds into its functional three-dimensional structure. Misfolding, on the other hand, can lead to various conformational diseases. Understanding and modeling these processes are essential for insights into protein function and the development of therapeutic interventions.

Key Insights

Theoretical and Computational Models:
- Simplified and all-atom models are used to investigate protein folding mechanisms, with lattice heteropolymer simulations and molecular dynamics (MD) simulations providing insights into folding intermediates and the role of water in unfolding .
- MD simulations complement experimental techniques by providing atomic details and often predict experimental outcomes, enhancing our understanding of protein dynamics and misfolding.
Folding Pathways and Mechanisms:
- There are two main views on protein folding: one suggests multiple unpredictable routes driven by an energetically downhill landscape, while the other proposes specific intermediates in a defined pathway.
- Cooperative structural units called foldons unfold and refold repeatedly, suggesting that foldons, not individual amino acids, are the unit steps in folding pathways. This sequential stabilization mechanism guides the formation of native-like structures.
Misfolding and Quality Assessment:
- Misfolding occurs when the polypeptide chain fails to achieve its native conformation, often leading to conformational diseases.
- Protein Folding Quality Assessment (PFQA) uses a three-parameter distribution function to assess the quality of protein folding, providing a mathematical framework to evaluate folding processes.

Conclusion

Research on protein folding and misfolding employs a combination of theoretical models, molecular dynamics simulations, and experimental techniques to unravel the complex mechanisms involved. Theoretical models and MD simulations offer detailed insights into folding intermediates and pathways, while the concept of foldons provides a structured view of the folding process. Misfolding, assessed through mathematical models like PFQA, highlights the importance of achieving the correct native conformation to prevent diseases. Together, these approaches enhance our understanding of protein folding dynamics and misfolding mechanisms.

How do we study and model protein folding and misfolding?

Summary

Introduction

Key Insights

Conclusion

Sources and full results

Theoretical studies of protein folding and unfolding.

Theoretical studies using both simplified and all-atom models reveal that protein folding and unfolding are influenced by a global energy minimum, providing insights for designing experiments to study the mechanisms in different proteins.

Understanding protein unfolding from molecular simulations

Molecular dynamics simulations and experimental biophysical techniques provide atomic resolution views of protein unfolding, advancing our understanding of protein folding and mechanical strength.

Protein folding and misfolding: mechanism and principles

Protein folding is primarily driven by cooperative native-like foldon units and sequential stabilization, with optional misfolding errors causing 3-state and heterogeneous kinetic folding.

Mathematics of protein pathological misfolding.

Protein Folding Quality Assessment (PFQA) is a three-parameter model that assesses protein folding quality, which is crucial for understanding and treating protein misfolding-related diseases.

From folding theories to folding proteins: a review and assessment of simulation studies of protein folding and unfolding.

Simulation studies of protein folding and unfolding can provide complementary details of folding mechanisms and thermodynamics, but success relies on adequate sampling of diverse conformational regions and multiple trajectories at multiple temperatures.

Protein-folding landscapes in multichain systems.

In multichain systems, proteins fold more preferentially into misfolded states, with native topology playing a role in early stages of aggregation.

Protein folding – simplicity in complexity

Protein folding is complex, but simple analytic models can capture the basic physics and predict fundamental limits for domain size and folding speed, potentially aiding in understanding and treating Alzheimer's disease.

Protein Folding and Misfolding on Surfaces

Surfaces can both facilitate protein folding and favor misfolding, resulting in different types of protein oligomers and polymers with different physical properties and cytotoxicities.

Protein Folding and Unfolding at Atomic Resolution

Atomic-level descriptions of protein folding and unfolding are now available, enabling predictions of protein folding events in cells using simulations benchmarked by experiment.

Protein Folding and Misfolding: A Perspective from Theory

Protein folding and misfolding are complex biological processes that influence health and disease, and understanding their mechanisms can lead to new protein design and structure predictions.

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