Open AccessUnfolding mechanism of thrombin-binding aptamer revealed by molecular dynamics simulation and Markov State Model
Author(s) -
Xiaojun Zeng,
Liyun Zhang,
Xincai Xiao,
Yuanyuan Jiang,
Yanzhi Guo,
Xinyan Yu,
Xuemei Pu,
Menglong Li
Publication year - 2016
Publication title -
scientific reports
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.24
H-Index - 213
ISSN - 2045-2322
DOI - 10.1038/srep24065
Subject(s) - folding (dsp implementation) , molecular dynamics , g quadruplex , chemistry , aptamer , population , biophysics , markov chain , protein folding , crystallography , computational biology , biology , biochemistry , computational chemistry , genetics , dna , computer science , demography , machine learning , sociology , electrical engineering , engineering
Thrombin-binding aptamer (TBA) with the sequence 5′GGTTGGTGTGGTTGG3′ could fold into G-quadruplex, which correlates with functionally important genomic regionsis. However, unfolding mechanism involved in the structural stability of G-quadruplex has not been satisfactorily elucidated on experiments so far. Herein, we studied the unfolding pathway of TBA by a combination of molecular dynamics simulation (MD) and Markov State Model (MSM). Our results revealed that the unfolding of TBA is not a simple two-state process but proceeds along multiple pathways with multistate intermediates. One high flux confirms some observations from NMR experiment. Another high flux exhibits a different and simpler unfolding pathway with less intermediates. Two important intermediate states were identified. One is similar to the G-triplex reported in the folding of G-quadruplex, but lack of H-bonding between guanines in the upper plane. More importantly, another intermediate state acting as a connector to link the folding region and the unfolding one, was the first time identified, which exhibits higher population and stability than the G-triplex-like intermediate. These results will provide valuable information for extending our understanding the folding landscape of G-quadruplex formation.