Modeling pK shift in DNA triplexes containing locked nucleic acids
The protonation states for nucleic acid bases are difficult to assess experimentally. In the context of DNA triplex, the protonation state of cytidine in the third strand is particularly important, because it needs to be protonated in order to form Hoogsteen hydrogen bonds. A sugar modification, loc...
| Main Authors: | , , , , |
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| Other Authors: | |
| Format: | Journal Article |
| Language: | English |
| Published: |
2019
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| Subjects: | |
| Online Access: | https://hdl.handle.net/10356/106398 http://hdl.handle.net/10220/49611 |
| _version_ | 1826118877267886080 |
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| author | Hartono, Yossa Dwi Xu, You Karshikoff, Andrey Nilsson, Lennart Villa, Alessandra |
| author2 | School of Biological Sciences |
| author_facet | School of Biological Sciences Hartono, Yossa Dwi Xu, You Karshikoff, Andrey Nilsson, Lennart Villa, Alessandra |
| author_sort | Hartono, Yossa Dwi |
| collection | NTU |
| description | The protonation states for nucleic acid bases are difficult to assess experimentally. In the context of DNA triplex, the protonation state of cytidine in the third strand is particularly important, because it needs to be protonated in order to form Hoogsteen hydrogen bonds. A sugar modification, locked nucleic acid (LNA), is widely used in triplex forming oligonucleotides to target sites in the human genome. In this study, the parameters for LNA are developed in line with the CHARMM nucleic acid force field and validated toward the available structural experimental data. In conjunction, two computational methods were used to calculate the protonation state of the third strand cytidine in various DNA triplex environments: λ-dynamics and multiple pH regime. Both approaches predict pK of this cytidine shifted above physiological pH when cytidine is in the third strand in a triplex environment. Both methods show an upshift due to cytidine methylation, and a small downshift when the sugar configuration is locked. The predicted pK values for cytidine in DNA triplex environment can inform the design of better-binding oligonucleotides. |
| first_indexed | 2024-10-01T04:50:43Z |
| format | Journal Article |
| id | ntu-10356/106398 |
| institution | Nanyang Technological University |
| language | English |
| last_indexed | 2024-10-01T04:50:43Z |
| publishDate | 2019 |
| record_format | dspace |
| spelling | ntu-10356/1063982023-02-28T16:56:42Z Modeling pK shift in DNA triplexes containing locked nucleic acids Hartono, Yossa Dwi Xu, You Karshikoff, Andrey Nilsson, Lennart Villa, Alessandra School of Biological Sciences DNA Triplexes Locked Nucleic Acids Science::Biological sciences The protonation states for nucleic acid bases are difficult to assess experimentally. In the context of DNA triplex, the protonation state of cytidine in the third strand is particularly important, because it needs to be protonated in order to form Hoogsteen hydrogen bonds. A sugar modification, locked nucleic acid (LNA), is widely used in triplex forming oligonucleotides to target sites in the human genome. In this study, the parameters for LNA are developed in line with the CHARMM nucleic acid force field and validated toward the available structural experimental data. In conjunction, two computational methods were used to calculate the protonation state of the third strand cytidine in various DNA triplex environments: λ-dynamics and multiple pH regime. Both approaches predict pK of this cytidine shifted above physiological pH when cytidine is in the third strand in a triplex environment. Both methods show an upshift due to cytidine methylation, and a small downshift when the sugar configuration is locked. The predicted pK values for cytidine in DNA triplex environment can inform the design of better-binding oligonucleotides. Published version 2019-08-13T07:40:15Z 2019-12-06T22:10:46Z 2019-08-13T07:40:15Z 2019-12-06T22:10:46Z 2018 Journal Article Hartono, Y. D., Xu, Y., Karshikoff, A., Nilsson, L., & Villa, A. (2018). Modeling pK shift in DNA triplexes containing locked nucleic acids. Journal of Chemical Information and Modeling, 58(4), 773-783. doi:10.1021/acs.jcim.7b00741 1549-9596 https://hdl.handle.net/10356/106398 http://hdl.handle.net/10220/49611 10.1021/acs.jcim.7b00741 en Journal of Chemical Information and Modeling © 2018 American Chemical Society. This is an open access article published under an ACS AuthorChoice License, which permits copying and redistribution of the article or any adaptations for non-commercial purposes. 11 p. application/pdf |
| spellingShingle | DNA Triplexes Locked Nucleic Acids Science::Biological sciences Hartono, Yossa Dwi Xu, You Karshikoff, Andrey Nilsson, Lennart Villa, Alessandra Modeling pK shift in DNA triplexes containing locked nucleic acids |
| title | Modeling pK shift in DNA triplexes containing locked nucleic acids |
| title_full | Modeling pK shift in DNA triplexes containing locked nucleic acids |
| title_fullStr | Modeling pK shift in DNA triplexes containing locked nucleic acids |
| title_full_unstemmed | Modeling pK shift in DNA triplexes containing locked nucleic acids |
| title_short | Modeling pK shift in DNA triplexes containing locked nucleic acids |
| title_sort | modeling pk shift in dna triplexes containing locked nucleic acids |
| topic | DNA Triplexes Locked Nucleic Acids Science::Biological sciences |
| url | https://hdl.handle.net/10356/106398 http://hdl.handle.net/10220/49611 |
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