title: Unfolding mechanism of thrombin-binding aptamer revealed by molecular dynamics simulation and Markov State Model.
abstract: 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.
authors.affiliation: Faculty of Chemistry, Sichuan University, Chengdu 610064, People's Republic of China.
authors.forename: Xiaojun
authors.initials: X
authors.lastname: Zeng
authors.affiliation: Faculty of Chemistry, Sichuan University, Chengdu 610064, People's Republic of China.
authors.forename: Liyun
authors.initials: L
authors.lastname: Zhang
authors.affiliation: Faculty of Chemistry, Sichuan University, Chengdu 610064, People's Republic of China.
authors.forename: Xiuchan
authors.initials: X
authors.lastname: Xiao
authors.affiliation: Faculty of Chemistry, Sichuan University, Chengdu 610064, People's Republic of China.
authors.forename: Yuanyuan
authors.initials: Y
authors.lastname: Jiang
authors.affiliation: Faculty of Chemistry, Sichuan University, Chengdu 610064, People's Republic of China.
authors.forename: Yanzhi
authors.initials: Y
authors.lastname: Guo
authors.affiliation: Faculty of Chemistry, Sichuan University, Chengdu 610064, People's Republic of China.
authors.forename: Xinyan
authors.initials: X
authors.lastname: Yu
authors.affiliation: Faculty of Chemistry, Sichuan University, Chengdu 610064, People's Republic of China.
authors.forename: Xuemei
authors.initials: X
authors.lastname: Pu
authors.affiliation: Faculty of Chemistry, Sichuan University, Chengdu 610064, People's Republic of China.
authors.forename: Menglong
authors.initials: M
authors.lastname: Li
mesh_terms: D000465:Algorithms; D052157:Aptamers, Nucleotide / Q000737:chemistry*; D054856:G-Quadruplexes; D006147:Guanine / Q000737:chemistry; D006801:Humans; D006860:Hydrogen Bonding; D007700:Kinetics; D009682:Magnetic Resonance Spectroscopy; D008390:Markov Chains; D056004:Molecular Dynamics Simulation; D011336:Probability; D011485:Protein Binding; D011489:Protein Denaturation; D017510:Protein Folding; D013696:Temperature; D013917:Thrombin / Q000737:chemistry*
chemical_list: D052157:Aptamers, Nucleotide; C081676:thrombin aptamer; D006147:Guanine; D013917:Thrombin