Molecular mechanism of anionic stabilizer for telomere G-quadruplex

Zhiguo Wang; Jianfeng Li; Jun Liu; Lihui Wang; Yanhua Lu; Jun-Ping Liu

doi:10.52601/bpr.2022.220039

Molecular mechanism of anionic stabilizer for telomere G-quadruplex

Biophys Rep. 2022 Aug 31;8(4):225-238. doi: 10.52601/bpr.2022.220039.

Authors

Zhiguo Wang¹, Jianfeng Li¹, Jun Liu¹, Lihui Wang¹, Yanhua Lu¹, Jun-Ping Liu^{1

2

3

4}

Affiliations

¹ Institute of Ageing Research, School of Basic Medical Sciences, Hangzhou Normal University, Hangzhou 311121, China.
² Department of Immunology, Central Eastern Clinical School, Monash University, Melbourne, Vitoria 3004, Australia.
³ Hudson Institute of Medical Research, Clayton, Victoria 3168, Australia.
⁴ Department of Molecular and Translational Science, Monash University, Clayton, Victoria 3168, Australia.

Abstract

Telomere DNA assumes a high-order G-quadruplex (G4) structure, stabilization of which prevents telomere lengthening by telomerase in cancer. Through applying combined molecular simulation methods, an investigation on the selective binding mechanism of anionic phthalocyanine 3,4',4'',4'''-tetrasulfonic acid (APC) and human hybrid (3 + 1) G4s was firstly performed at the atomic level. Compared to the groove binding mode of APC and the hybrid type I (hybrid-I) telomere G4, APC preferred to bind to the hybrid type II (hybrid-II) telomere G4 via end-stacking interactions, which showed much more favorable binding free energies. Analyses of the non-covalent interaction and binding free energy decomposition revealed a decisive role of van der Waals interaction in the binding of APC and telomere hybrid G4s. And the binding of APC and hybrid-II G4 that showed the highest binding affinity adopted the end-stacking binding mode to form the most extensive van der Waals interactions. These findings add new knowledge to the design of selective stabilizers targeting telomere G4 in cancer.

Keywords: Anionic stabilizer; MM/GBSA; Molecular dynamics; Selective mechanism; Telomere G-quadruplex.