Abstract:
:DB2277, a heterocyclic diamidine, is a successful design for mixed base pair (bp) DNA sequence recognition. The compound has a central aza-benzimidazole group that forms two H-bonds with a GC bp that has flanking AT bps. The nuclear magnetic resonance structure of the DB2277-DNA complex with an AAGATA recognition site sequence was determined, and here we report extended molecular dynamics (MD) simulations of the structure. DB2277 has two terminal phenyl-amidine groups, one of which is directly linked to the DB2277 heterocyclic core and the other through a flexible -OCH2- group. The flexibly linked phenyl is too far from the minor groove floor to make direct H-bonds but is linked to an AT bp through water-mediated H-bonds. The flexibly linked phenyl-amidine with water-mediated H-bonds to the bases at the floor of the minor groove suggested that it might rotate in time spans accessible in MD. To test this idea, we conducted multimicrosecond MD simulations to determine if these phenyl rotations could be observed for a bound compound. In a 3 μs simulation, highly dynamic torsional motions were observed for the -OCH2-linked phenyl but not for the other phenyl. The dynamics periodically reached a level to allow 180° rotation of the phenyl while it was still bound in the minor groove. This is the first observation of rotation of a phenyl bound to DNA, and the results provide mechanistic details about how a rotation can occur as well as how mixed bp recognition can occur for monomer compounds bound to the minor groove.
journal_name
Biochemistryjournal_title
Biochemistryauthors
Harika NK,Wilson WDdoi
10.1021/acs.biochem.8b00647subject
Has Abstractpub_date
2018-08-21 00:00:00pages
5050-5057issue
33eissn
0006-2960issn
1520-4995journal_volume
57pub_type
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