Abstract：
: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 p K 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 p K values for cytidine in DNA triplex environment can inform the design of better-binding oligonucleotides.
journal_name
J Chem Inf Modeljournal_title
Journal of chemical information and modelingauthors
Hartono YD,Xu Y,Karshikoff A,Nilsson L,Villa Adoi
10.1021/acs.jcim.7b00741subject
Has Abstractpub_date
2018-04-23 00:00:00pages
773-783issue
4eissn
1549-9596issn
1549-960Xjournal_volume
58pub_type
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