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Mechanistic insight into ligand binding to G-quadruplex DNA.

Abstract：

:Specific guanine-rich regions in human genome can form higher-order DNA structures called G-quadruplexes, which regulate many relevant biological processes. For instance, the formation of G-quadruplex at telomeres can alter cellular functions, inducing apoptosis. Thus, developing small molecules that are able to bind and stabilize the telomeric G-quadruplexes represents an attractive strategy for antitumor therapy. An example is 3-(benzo[d]thiazol-2-yl)-7-hydroxy-8-((4-(2-hydroxyethyl)piperazin-1-yl)methyl)-2H-chromen-2-one (compound 1: ), recently identified as potent ligand of the G-quadruplex [d(TGGGGT)]4 with promising in vitro antitumor activity. The experimental observations are suggestive of a complex binding mechanism that, despite efforts, has defied full characterization. Here, we provide through metadynamics simulations a comprehensive understanding of the binding mechanism of 1: to the G-quadruplex [d(TGGGGT)]4. In our calculations, the ligand explores all the available binding sites on the DNA structure and the free-energy landscape of the whole binding process is computed. We have thus disclosed a peculiar hopping binding mechanism whereas 1: is able to bind both to the groove and to the 3' end of the G-quadruplex. Our results fully explain the available experimental data, rendering our approach of great value for further ligand/DNA studies.

journal_name

Nucleic Acids Res

journal_title

Nucleic acids research

authors

Di Leva FS,Novellino E,Cavalli A,Parrinello M,Limongelli V

doi

10.1093/nar/gku247

subject

Has Abstract

pub_date

2014-05-01 00:00:00

pages

5447-55

issue

9

eissn

0305-1048

issn

1362-4962

pii

gku247

journal_volume

42

pub_type

杂志文章

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