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On the computational modelling of prolyl–peptide cis–trans Isomerisation: benchmarking DFT approaches with N–acetylproline methylamide
Thesis (MSc)--Stellenbosch University, 2025.
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| Format: | Thesis |
| Language: | English |
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Stellenbosch : Stellenbosch University
2025
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| _version_ | 1867614019067576320 |
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| access_status_str | Open Access |
| author | Lategan, Francois Adriaan |
| author2 | Patterton, Hugh–George |
| author_browse | Lategan, Francois Adriaan Patterton, Hugh–George |
| author_facet | Patterton, Hugh–George Lategan, Francois Adriaan |
| author_sort | Lategan, Francois Adriaan |
| collection | Thesis |
| dc_rights_str_mv | Stellenbosch University |
| description | Thesis (MSc)--Stellenbosch University, 2025. |
| format | Thesis |
| id | oai:scholar.sun.ac.za:10019.1/134669 |
| institution | Stellenbosch University (South Africa) |
| language | English |
| last_indexed | 2026-06-10T12:45:22.846Z |
| license_str | Other — see source repository |
| provenance_str_mv | Harvested via OAI-PMH from SUNScholar — Stellenbosch University Repository |
| publishDate | 2025 |
| publishDateRange | 2025 |
| publishDateSort | 2025 |
| publisher | Stellenbosch : Stellenbosch University |
| publisherStr | Stellenbosch : Stellenbosch University |
| record_format | dspace |
| source_str | SUNScholar — Stellenbosch University Repository |
| spelling | oai:scholar.sun.ac.za:10019.1/134669 On the computational modelling of prolyl–peptide cis–trans Isomerisation: benchmarking DFT approaches with N–acetylproline methylamide Lategan, Francois Adriaan Patterton, Hugh–George Stellenbosch University. Faculty of Science. Centre for Bioinformatics & Computational Biology Protein folding -- Computer simulation Peptides -- Conformation Isomerization Molecular dynamics -- Computer simulation Proline -- Computer simulation Computational chemistry -- Technique Density functionals -- Computer simulation UCTD Thesis (MSc)--Stellenbosch University, 2025. Lategan, F. A. 2025. On the Computational Modelling of Prolyl–Peptide cis–trans Isomerisation: Benchmarking DFT Approaches with N–Acetylproline Methylamide. Unpublished masters thesis. Stellenbosch: Stellenbosch University [online]. Available: https://scholar.sun.ac.za/items/b52dcc6a-7b51-444b-baec-4960b114de8d ENGLISH ABSTRACT: Isomerisation about the peptide bond preceding proline residues is a rate–limiting step in protein folding. The enzymatic catalysis of this process has broad implications for immune regulation, cell proliferation, neurodegenerative disease and oncogenesis. The large molecular size and conformational freedom of proteins pose a significant challenge for the accurate computational modelling of these processes, since the computational complexity of molecular models grows exponentially with system size. Finite computational resources necessitate the careful selection of efficient computational strategies if we are to understand the mechanisms that drive the folding of proline–containing proteins. This study investigates N–acetylproline N’–methylamide (AcProNHMe) as a minimal model of prolyl peptides in proteins to establish best practices for the computational modelling of isomerisation reactions. The small size of AcProNHMe moderates its computational complexity, while its pyrrolidine ring, C–terminal hydrogen donor, and neutral termini mimic the structure of prolyl residues found in proteins. Qualitative comparisons between the conformational landscapes of AcProNHMe — modelled with different implicit solvents — and the conformational distribution of prolyl residues in the Protein Data Bank confirm that solvent models are critical for accurately reproducing the conformational energies of these residues. Three–dimensional potential energy surface scans using the GFN2–xTB semi–empirical method elucidate the roles of hydrogen bonding, steric repulsion and an 𝑛→𝜋∗ interaction along the reaction path. Density Functional Theory (DFT) provides physically rigorous estimates of the energies at the critical points in the reaction pathways, but careful benchmarking is essential for robust accuracy. A benchmark of seven density functional approximations against CCSD(T)/CBS single point energies reveals that local meta–GGA functionals with double–ζ basis sets are suitable for geometry optimisation and reaction energy estimation. These functionals, however, often overestimate barrier heights by more than 2 kcal⋅mol−1. Range–separated hybrid functionals estimate reaction barriers particularly well, with the ωB97M functional consistently achieving sub–kcal⋅mol−1 accuracy. The def2–TZVPP basis set is sufficient for accurate barrier heights. Notably, both DFT–D and VV10 dispersion corrections overcorrect the dispersion energy of this small model system. This work culminates in actionable recommendations for the selection of DFT frameworks to model prolyl–peptide isomerisation accurately in larger polypeptides. These recommendations may facilitate the accurate description of chaperone protein mechanisms and guide the design of efficient artificial isomerases. AFRIKAANSE OPSOMMING: Geen opsomming beskikbaar. Masters 2025-12-22T14:08:19Z 2025-12-22T14:08:19Z 2025-12 Thesis https://scholar.sun.ac.za/handle/10019.1/134669 en Stellenbosch University 147 pages : illustrations application/pdf Stellenbosch : Stellenbosch University |
| spellingShingle | Protein folding -- Computer simulation Peptides -- Conformation Isomerization Molecular dynamics -- Computer simulation Proline -- Computer simulation Computational chemistry -- Technique Density functionals -- Computer simulation UCTD Lategan, Francois Adriaan On the computational modelling of prolyl–peptide cis–trans Isomerisation: benchmarking DFT approaches with N–acetylproline methylamide |
| title | On the computational modelling of prolyl–peptide cis–trans Isomerisation: benchmarking DFT approaches with N–acetylproline methylamide |
| title_full | On the computational modelling of prolyl–peptide cis–trans Isomerisation: benchmarking DFT approaches with N–acetylproline methylamide |
| title_fullStr | On the computational modelling of prolyl–peptide cis–trans Isomerisation: benchmarking DFT approaches with N–acetylproline methylamide |
| title_full_unstemmed | On the computational modelling of prolyl–peptide cis–trans Isomerisation: benchmarking DFT approaches with N–acetylproline methylamide |
| title_short | On the computational modelling of prolyl–peptide cis–trans Isomerisation: benchmarking DFT approaches with N–acetylproline methylamide |
| title_sort | on the computational modelling of prolyl peptide cis trans isomerisation benchmarking dft approaches with n acetylproline methylamide |
| topic | Protein folding -- Computer simulation Peptides -- Conformation Isomerization Molecular dynamics -- Computer simulation Proline -- Computer simulation Computational chemistry -- Technique Density functionals -- Computer simulation UCTD |
| url | https://scholar.sun.ac.za/handle/10019.1/134669 |
| work_keys_str_mv | AT lateganfrancoisadriaan onthecomputationalmodellingofprolylpeptidecistransisomerisationbenchmarkingdftapproacheswithnacetylprolinemethylamide |