Benchmarking of force fields to characterize the intrinsically disordered R2-FUS-LC region
Abstract Intrinsically Disordered Proteins (IDPs) play crucial roles in numerous diseases like Alzheimer's and ALS by forming irreversible amyloid fibrils. The effectiveness of force fields (FFs) developed for globular proteins and their modified versions for IDPs varies depending on the specif...
| Main Authors: | , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
Nature Portfolio
2023-08-01
|
| Series: | Scientific Reports |
| Online Access: | https://doi.org/10.1038/s41598-023-40801-6 |
| _version_ | 1797576689365024768 |
|---|---|
| author | Maud Chan-Yao-Chong Justin Chan Hidetoshi Kono |
| author_facet | Maud Chan-Yao-Chong Justin Chan Hidetoshi Kono |
| author_sort | Maud Chan-Yao-Chong |
| collection | DOAJ |
| description | Abstract Intrinsically Disordered Proteins (IDPs) play crucial roles in numerous diseases like Alzheimer's and ALS by forming irreversible amyloid fibrils. The effectiveness of force fields (FFs) developed for globular proteins and their modified versions for IDPs varies depending on the specific protein. This study assesses 13 FFs, including AMBER and CHARMM, by simulating the R2 region of the FUS-LC domain (R2-FUS-LC region), an IDP implicated in ALS. Due to the flexibility of the region, we show that utilizing multiple measures, which evaluate the local and global conformations, and combining them together into a final score are important for a comprehensive evaluation of force fields. The results suggest c36m2021s3p with mTIP3p water model is the most balanced FF, capable of generating various conformations compatible with known ones. In addition, the mTIP3P water model is computationally more efficient than those of top-ranked AMBER FFs with four-site water models. The evaluation also reveals that AMBER FFs tend to generate more compact conformations compared to CHARMM FFs but also more non-native contacts. The top-ranking AMBER and CHARMM FFs can reproduce intra-peptide contacts but underperform for inter-peptide contacts, indicating there is room for improvement. |
| first_indexed | 2024-03-10T21:57:21Z |
| format | Article |
| id | doaj.art-52adee96b2874f82a229a0ea219cad91 |
| institution | Directory Open Access Journal |
| issn | 2045-2322 |
| language | English |
| last_indexed | 2024-03-10T21:57:21Z |
| publishDate | 2023-08-01 |
| publisher | Nature Portfolio |
| record_format | Article |
| series | Scientific Reports |
| spelling | doaj.art-52adee96b2874f82a229a0ea219cad912023-11-19T13:04:23ZengNature PortfolioScientific Reports2045-23222023-08-0113111210.1038/s41598-023-40801-6Benchmarking of force fields to characterize the intrinsically disordered R2-FUS-LC regionMaud Chan-Yao-Chong0Justin Chan1Hidetoshi Kono2Molecular Modeling and Simulation (MMS) Team, Institute for Quantum Life Science, National Institutes for Quantum Science and Technology (QST)Molecular Modeling and Simulation (MMS) Team, Institute for Quantum Life Science, National Institutes for Quantum Science and Technology (QST)Molecular Modeling and Simulation (MMS) Team, Institute for Quantum Life Science, National Institutes for Quantum Science and Technology (QST)Abstract Intrinsically Disordered Proteins (IDPs) play crucial roles in numerous diseases like Alzheimer's and ALS by forming irreversible amyloid fibrils. The effectiveness of force fields (FFs) developed for globular proteins and their modified versions for IDPs varies depending on the specific protein. This study assesses 13 FFs, including AMBER and CHARMM, by simulating the R2 region of the FUS-LC domain (R2-FUS-LC region), an IDP implicated in ALS. Due to the flexibility of the region, we show that utilizing multiple measures, which evaluate the local and global conformations, and combining them together into a final score are important for a comprehensive evaluation of force fields. The results suggest c36m2021s3p with mTIP3p water model is the most balanced FF, capable of generating various conformations compatible with known ones. In addition, the mTIP3P water model is computationally more efficient than those of top-ranked AMBER FFs with four-site water models. The evaluation also reveals that AMBER FFs tend to generate more compact conformations compared to CHARMM FFs but also more non-native contacts. The top-ranking AMBER and CHARMM FFs can reproduce intra-peptide contacts but underperform for inter-peptide contacts, indicating there is room for improvement.https://doi.org/10.1038/s41598-023-40801-6 |
| spellingShingle | Maud Chan-Yao-Chong Justin Chan Hidetoshi Kono Benchmarking of force fields to characterize the intrinsically disordered R2-FUS-LC region Scientific Reports |
| title | Benchmarking of force fields to characterize the intrinsically disordered R2-FUS-LC region |
| title_full | Benchmarking of force fields to characterize the intrinsically disordered R2-FUS-LC region |
| title_fullStr | Benchmarking of force fields to characterize the intrinsically disordered R2-FUS-LC region |
| title_full_unstemmed | Benchmarking of force fields to characterize the intrinsically disordered R2-FUS-LC region |
| title_short | Benchmarking of force fields to characterize the intrinsically disordered R2-FUS-LC region |
| title_sort | benchmarking of force fields to characterize the intrinsically disordered r2 fus lc region |
| url | https://doi.org/10.1038/s41598-023-40801-6 |
| work_keys_str_mv | AT maudchanyaochong benchmarkingofforcefieldstocharacterizetheintrinsicallydisorderedr2fuslcregion AT justinchan benchmarkingofforcefieldstocharacterizetheintrinsicallydisorderedr2fuslcregion AT hidetoshikono benchmarkingofforcefieldstocharacterizetheintrinsicallydisorderedr2fuslcregion |