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Updated: Oct 3, 2025
Characterizing Individual Protein Aggregates by Infrared Nanospectroscopy and Atomic Force Microscopy
Published on: September 12, 2019
Probing Protein Aggregation Using the Coarse-Grained UNRES Force Field
Ana V Rojas1, Gia G Maisuradze2, Harold A Scheraga2
1Schrodinger Inc., 120 West 45th Street New York, New York, 10036, NY, USA.
Abstract:
Protein aggregation is the cause of many, often lethal, diseases, including the Alzheimer's, Parkinson's, and Huntington's diseases, and familial amyloidosis. Theoretical investigation of the mechanism of this process, including the structures of the oligomeric intermediates which are the most toxic, is difficult because of long time scale of aggregation. Coarse-grained models, which enable us to extend the simulation time scale by three or more orders of magnitude, are, therefore, of great advantage in such studies. In this chapter, we describe the application of the physics-based UNited RESidue (UNRES) force field developed in our laboratory to study protein aggregation, in both free simulations and simulations of aggregation propagation from an existing template (seed), and illustrate it with the examples of Aβ-peptide aggregation and Aβ-peptide-assisted aggregation of the peptides derived from the repeat domains of tau (TauRD).
Insights
Investigating protein aggregation, a cause of neurodegenerative diseases, is challenging due to long timescales. This study uses coarse-grained models and the UNRES force field to simulate protein aggregation, aiding in understanding disease mechanisms.
Area of Science:
- Biophysics
- Computational Biology
- Molecular Medicine
Background:
- Protein aggregation is implicated in lethal diseases like Alzheimer's and Parkinson's.
- Understanding the toxic oligomeric intermediates of protein aggregation is crucial.
- Simulating these processes is difficult due to the extensive timescales involved.
Purpose of the Study:
- To apply the physics-based UNited RESidue (UNRES) force field for protein aggregation studies.
- To investigate protein aggregation mechanisms using coarse-grained models.
- To simulate both free and seeded aggregation processes.
Main Methods:
- Utilized coarse-grained modeling to extend simulation timescales by orders of magnitude.
- Applied the UNRES force field for physics-based simulations of protein aggregation.
- Performed simulations of amyloid-beta (Aβ) peptide aggregation and tau (TauRD) peptide aggregation.
Main Results:
- Demonstrated the utility of UNRES force field in simulating protein aggregation.
- Successfully modeled Aβ-peptide aggregation.
- Showcased Aβ-peptide-assisted aggregation of TauRD peptides.
Conclusions:
- Coarse-grained models, specifically UNRES, are advantageous for studying protein aggregation.
- The UNRES force field can effectively simulate complex aggregation pathways.
- This approach provides insights into the mechanisms of protein misfolding diseases.
