Тип публикации: статья из журнала

Год издания: 2023

Идентификатор DOI: 10.1021/acs.biochem.3c00327

Аннотация: Several efforts are currently directed at the creation and cellular implementation of alternative genetic systems composed of pairing components that are orthogonal to the natural dA/dT and dG/dC base pairs. In an alternative approach, Watson–Crick-type pairing is conserved, but one or all of the four letters of the A, C, G, and T Показать полностьюalphabet are substituted by modified components. Thus, all four nucleobases were altered to create halogenated deazanucleic acid (DZA): dA was replaced by 7-deaza-2′-deoxyadenosine (dzA), dG by 7-deaza-2′-deoxyguanosine (dzG), dC by 5-fluoro-2′-deoxycytidine (FdC), and dT by 5-chloro-2′-deoxyuridine (CldU). This base-pairing system was previously shown to retain function in Escherichia coli. Here, we analyze the stability, hydration, structure, and dynamics of a DZA Dickerson–Drew Dodecamer (DDD) of sequence 5′-FdC-dzG-FdC-dzG-dzA-dzA-CldU-CldU-FdC-dzG-FdC-dzG-3′. Contrary to similar stabilities of DDD and DZA-DDD, osmotic stressing revealed a dramatic loss of hydration for the DZA-DDD relative to that for the DDD. The parent DDD 5′-d(CGCGAATTCGCG)-3′ features an A-tract, a run of adenosines uninterrupted by a TpA step, and exhibits a hallmark narrow minor groove. Crystal structures─in the presence of RNase H─and MD simulations show increased conformational plasticity ("morphing") of DZA-DDD relative to that of the DDD. The narrow dzA-tract minor groove in one structure widens to resemble that in canonical B-DNA in a second structure. These changes reflect an indirect consequence of altered DZA major groove electrostatics (less negatively polarized compared to that in DNA) and hydration (reduced compared to that in DNA). Therefore, chemical modifications outside the minor groove that lead to collapse of major groove electrostatics and hydration can modulate A-tract geometry.

Журнал: Biochemistry

Выпуск журнала: Т. 62, № 19

Номера страниц: 2854-2867

ISSN журнала: 00062960

Издатель: American Chemical Society

• Pallan Pradeep S. (School of Medicine, Department of Biochemistry, and Center for Structural Biology, Vanderbilt University, Nashville, Tennessee 37232, United States)
• Lybrand Terry P. (Department of Chemistry and Center for Structural Biology, Vanderbilt University, Nashville, Tennessee 37232, United States)
• Rozners Eriks (Department of Chemistry, Binghamton University, Binghamton, New York 13902, United States)
• Abramov Mikhail (Laboratory of Medicinal Chemistry, KU Leuven, Rega Institute for Medical Research, Minderbroedersstraat 10, Leuven 3000, Belgium)
• Schepers Guy (Laboratory of Medicinal Chemistry, KU Leuven, Rega Institute for Medical Research, Minderbroedersstraat 10, Leuven 3000, Belgium)
• Eremeeva Elena (Laboratory of Medicinal Chemistry, KU Leuven, Rega Institute for Medical Research, Minderbroedersstraat 10, Leuven 3000, Belgium)
• Herdewijn Piet (Laboratory of Medicinal Chemistry, KU Leuven, Rega Institute for Medical Research, Minderbroedersstraat 10, Leuven 3000, Belgium)
• Egli Martin (School of Medicine, Department of Biochemistry, and Center for Structural Biology, Vanderbilt University, Nashville, Tennessee 37232, United States)

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