Molecular recognition of DNA base pairs by the formamido/pyrrole and formamido/imidazole pairings in stacked polyamides

Abstract

Polyamides containing an N-terminal formamido (f) group bind to the minor groove of DNA as staggered, antiparallel dimers in a sequence-specific manner. The formamido group increases the affinity and binding site size, and it promotes the molecules to stack in a staggered fashion thereby pairing itself with either a pyrrole (Py) or an imidazole (Im). There has not been a systematic study on the DNA recognition properties of the f/Py and f/Im terminal pairings. These pairings were analyzed here in the context of f-ImPyPy, f-ImPyIm, f-PyPyPy and f-PyPyIm, which contain the central pairing modes, –ImPy– and –PyPy–. The specificity of these triamides towards symmetrical recognition sites allowed for the f/Py and f/Im terminal pairings to be directly compared by SPR, CD and ΔTM experiments. The f/Py pairing, when placed next to the –ImPy– or –PyPy– central pairings, prefers A/T and T/A base pairs to G/C base pairs, suggesting that f/Py has similar DNA recognition specificity to Py/Py. With –ImPy– central pairings, f/Im prefers C/G base pairs (>10 times) to the other Watson–Crick base pairs; therefore, f/Im behaves like the Py/Im pair. However, the f/Im pairing is not selective for the C/G base pair when placed next to the –PyPy– central pairings.

Survey of the year 2005 commercial optical biosensor literature

“…These articles exemplify today's state-of-the-art applications in biosensor studies and range from wellexecuted, qualitative [184,294], kinetic [429, 475,664,704,776,779,906,907], and equilibrium analyses [664,751,906,907] to the use of novel assay designs [526] and new technology [583]. Even more importantly, these articles illustrate the quality of data and interpretation that we expect to see in biosensor-based studies.…”

“…In an effort to tackle parasites that target DNA, as well as to understand molecular mechanisms of DNA recognition, Wilson and coworkers are developing new compounds that bind specific DNA sequences [ 664,751,776]. Much of the work published by these researchers requires fitting to complex models, but without fail they perform supporting experiments to justify the complexity they observe in some systems.…”

“…Buchmueller et al [664] applied both kinetic and equilibrium analyses to investigate how pyrrole compounds target specific DNA sequences. In the example shown in Figure 8C, the compound displayed an affinity for TGCA hairpin almost 100 times higher than for CGCG and TCGA hairpins.…”

The intricacies of the stacking interaction in a pyrrole–pyrrole system

“…A pyrrole molecule (unlike pyridine one) possesses its nitrogen atom connected to a hydrogen atom and relative to benzene with six p-electrons in its carbon framework, it possesses six p-electrons distributed over five atoms. Hence, as a heteroatomic planar and electronrich ring, it is a useful recognition element in many biological contexts in which it may be engaged in creation of different sorts of NCI such as hydrogen bonds and pstacking [32,33]. Pyrrole-containing molecules include commonly naturally produced compounds such as chlorophyll, chlorins, vitamin B12 and porphyrinogens [34][35][36].…”

Dynamic hydrogen bonding and DNA flexibility in minor groove binders: molecular dynamics simulation of the polyamide f‐ImPyIm bound to the Mlu1 (MCB) sequence 5′‐ACGCGT‐3′ in 2:1 motif

“…In addition to determining the equilibrium constants and kinetics of binding, surface plasmon resonance experiments indicate that f‐ImPyIm binds to 5′‐ACGCGT‐3′ in a 2:1 motif with two polyamides per DNA segment. Experimentally, this is indicated by response at saturation (RU sat ) that is twice the value expected for the formation of the 1:1 complex (Buchmueller et al ., ). NMR studies support this conclusion for other polyamides, including distamycin, and indicate that 2:1 binding is prominent even at low concentration of polyamide in solution indicating cooperative binding (Pelton and Wemmer, ; Mrksich et al ., ; Trauger et al ., ).…”