Insights into the free energy landscape and salt-controlled mechanism of the conformational conversions between human telomeric G-quadruplex structures.

G-quadruplexes have become attractive drug targets in cancer therapy. However, due to the polymorphism of G-quadruplex structures, it is difficult to experimentally verify the relevant structures of multiple intermediates and transition states in dynamic equilibrium. Hence, understanding the mechanism by which structural conversions of G-quadruplexes occur is still challenging. We conducted targeted molecular dynamics simulation with umbrella sampling to investigate how salt affects the conformational conversion of human telomeric G-quadruplex. Our results explore a unique view into the structures and energy barrier of the intermediates and transition states in the interconversion process. The pathway of G-quadruplex conformational interconversion was mapped out by a free energy landscape, consisting of branched parallel pathways with multiple energy basins. We propose a salt-controlled mechanism that as the salt concentration increases, the conformational conversion mechanism switches from multi-pathway folding to sequential folding pathways. The hybrid-I and hybrid-II structures are intermediates in the basket-propeller transformation. In high-salt solutions, the conformational conversion upon K binding is more feasible than upon Na binding. The free energy barrier for conformational conversions ranges from 1.6 to 4.6 kcal/mol. Our work will be beneficial in developing anticancer agents.

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