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The Effect of Molecular Crowding on the Stability of Human c-MYC Promoter Sequence I-Motif at Neutral pH
Department of Chemistry, Mississippi State University, Mississippi State, MS 39762, USA
* Author to whom correspondence should be addressed.
Received: 16 August 2013; in revised form: 26 September 2013 / Accepted: 10 October 2013 / Published: 15 October 2013
Abstract: We have previously shown that c-MYC promoter sequences can form stable i-motifs in acidic solution (pH 4.5–5.5). In terms of drug targeting, the question is whether c-MYC promoter sequence i-motifs will exist in the nucleus at neutral pH. In this work, we have investigated the stability of a mutant c-MYC i-motif in solutions containing a molecular crowding agent. The crowded nuclear environment was modeled by the addition of up to 40% w/w polyethylene glycols having molecular weights up to 12,000 g/mol. CD and DSC were used to establish the presence and stability of c-MYC i-motifs in buffer solutions over the pH range 4 to 7. We have shown that the c-MYC i-motif can exist as a stable structure at pH values as high as 6.7 in crowded solutions. Generic dielectric constant effects, e.g., a shift in the pKa of cytosine by more than 2 units (e.g., 4.8 to 7.0), or the formation of non-specific PEG/DNA complexes appear to contribute insignificantly to i-motif stabilization. Molecular crowding, largely an excluded volume effect of added PEG, having a molecular weight in excess of 1,000 g/mol, appears to be responsible for stabilizing the more compact i-motif over the random coil at higher pH values.
Keywords: i-motif; stability; neutral pH; molecular crowding; excluded volume effect
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Cui, J.; Waltman, P.; Le, V.H.; Lewis, E.A. The Effect of Molecular Crowding on the Stability of Human c-MYC Promoter Sequence I-Motif at Neutral pH. Molecules 2013, 18, 12751-12767.
Cui J, Waltman P, Le VH, Lewis EA. The Effect of Molecular Crowding on the Stability of Human c-MYC Promoter Sequence I-Motif at Neutral pH. Molecules. 2013; 18(10):12751-12767.
Cui, Jingjing; Waltman, Phillip; Le, Vu H.; Lewis, Edwin A. 2013. "The Effect of Molecular Crowding on the Stability of Human c-MYC Promoter Sequence I-Motif at Neutral pH." Molecules 18, no. 10: 12751-12767.