Large-scale QM/MM free energy simulations of enzyme catalysis reveal the influence of charge transfer
Hybrid quantum mechanical-molecular mechanical (QM/MM) simulations provide key insights into enzyme structure-function relationships. Numerous studies have demonstrated that large QM regions are needed to systematically converge ground state, zero temperature properties with electrostatic embedding...
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| Format: | Article |
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Royal Society of Chemistry (RSC)
2018
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| Online Access: | http://hdl.handle.net/1721.1/117500 https://orcid.org/0000-0001-9342-0191 |
| _version_ | 1811069655169630208 |
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| author | Kulik, Heather Janine |
| author2 | Massachusetts Institute of Technology. Department of Chemical Engineering |
| author_facet | Massachusetts Institute of Technology. Department of Chemical Engineering Kulik, Heather Janine |
| author_sort | Kulik, Heather Janine |
| collection | MIT |
| description | Hybrid quantum mechanical-molecular mechanical (QM/MM) simulations provide key insights into enzyme structure-function relationships. Numerous studies have demonstrated that large QM regions are needed to systematically converge ground state, zero temperature properties with electrostatic embedding QM/MM. However, it is not well known if ab initio QM/MM free energy simulations have this same dependence, in part due to the hundreds of thousands of energy evaluations required for free energy estimations that in turn limit QM region size. Here, we leverage recent advances in electronic structure efficiency and accuracy to carry out range-separated hybrid density functional theory free energy simulations in a representative methyltransferase. By studying 200 ps of ab initio QM/MM dynamics for each of five QM regions from minimal (64 atoms) to one-sixth of the protein (544 atoms), we identify critical differences between large and small QM region QM/MM in charge transfer between substrates and active site residues as well as in geometric structure and dynamics that coincide with differences in predicted free energy barriers. Distinct geometric and electronic structure features in the largest QM region indicate that important aspects of enzymatic rate enhancement in methyltransferases are identified with large-scale electronic structure. |
| first_indexed | 2024-09-23T08:13:49Z |
| format | Article |
| id | mit-1721.1/117500 |
| institution | Massachusetts Institute of Technology |
| last_indexed | 2024-09-23T08:13:49Z |
| publishDate | 2018 |
| publisher | Royal Society of Chemistry (RSC) |
| record_format | dspace |
| spelling | mit-1721.1/1175002022-09-30T08:28:41Z Large-scale QM/MM free energy simulations of enzyme catalysis reveal the influence of charge transfer Kulik, Heather Janine Massachusetts Institute of Technology. Department of Chemical Engineering Kulik, Heather Janine Hybrid quantum mechanical-molecular mechanical (QM/MM) simulations provide key insights into enzyme structure-function relationships. Numerous studies have demonstrated that large QM regions are needed to systematically converge ground state, zero temperature properties with electrostatic embedding QM/MM. However, it is not well known if ab initio QM/MM free energy simulations have this same dependence, in part due to the hundreds of thousands of energy evaluations required for free energy estimations that in turn limit QM region size. Here, we leverage recent advances in electronic structure efficiency and accuracy to carry out range-separated hybrid density functional theory free energy simulations in a representative methyltransferase. By studying 200 ps of ab initio QM/MM dynamics for each of five QM regions from minimal (64 atoms) to one-sixth of the protein (544 atoms), we identify critical differences between large and small QM region QM/MM in charge transfer between substrates and active site residues as well as in geometric structure and dynamics that coincide with differences in predicted free energy barriers. Distinct geometric and electronic structure features in the largest QM region indicate that important aspects of enzymatic rate enhancement in methyltransferases are identified with large-scale electronic structure. 2018-08-24T14:24:36Z 2018-08-24T14:24:36Z 2018-06 2018-07 2018-08-22T15:04:38Z Article http://purl.org/eprint/type/JournalArticle 1463-9076 1463-9084 http://hdl.handle.net/1721.1/117500 Kulik, Heather J. “Large-Scale QM/MM Free Energy Simulations of Enzyme Catalysis Reveal the Influence of Charge Transfer.” Physical Chemistry Chemical Physics 20, 31 (2018): 20650–20660 https://orcid.org/0000-0001-9342-0191 http://dx.doi.org/10.1039/c8cp03871f Physical Chemistry Chemical Physics Creative Commons Attribution-NonCommercial 3.0 Unported https://creativecommons.org/licenses/by-nc/3.0/ application/pdf Royal Society of Chemistry (RSC) Royal Society of Chemistry |
| spellingShingle | Kulik, Heather Janine Large-scale QM/MM free energy simulations of enzyme catalysis reveal the influence of charge transfer |
| title | Large-scale QM/MM free energy simulations of enzyme catalysis reveal the influence of charge transfer |
| title_full | Large-scale QM/MM free energy simulations of enzyme catalysis reveal the influence of charge transfer |
| title_fullStr | Large-scale QM/MM free energy simulations of enzyme catalysis reveal the influence of charge transfer |
| title_full_unstemmed | Large-scale QM/MM free energy simulations of enzyme catalysis reveal the influence of charge transfer |
| title_short | Large-scale QM/MM free energy simulations of enzyme catalysis reveal the influence of charge transfer |
| title_sort | large scale qm mm free energy simulations of enzyme catalysis reveal the influence of charge transfer |
| url | http://hdl.handle.net/1721.1/117500 https://orcid.org/0000-0001-9342-0191 |
| work_keys_str_mv | AT kulikheatherjanine largescaleqmmmfreeenergysimulationsofenzymecatalysisrevealtheinfluenceofchargetransfer |