Umbrella sampling molecular dynamics simulations reveal concerted ion movement through G-quadruplex DNA channels

Abstract

We have applied the umbrella sampling (US) method in all-atom molecular dynamics (MD) simulations to obtain potential of mean force (PMF) profiles for ion transport through three representative G-quadruplex DNA channels: [d(TG₄T)]₄, [d(G₃T₄G₄)]₂, and d[G₄(T₄G₄)₃]. The US MD results are in excellent agreement with those obtained previously with the adaptive biasing force (ABF) method. We then utilized the unique features in the US MD method to investigate multi-ion effects in [d(G₃T₄G₄)]₂ and discovered that the concerted ion movement is crucial for fully explaining the unusual experimental results on ion movement in this particular G-quadruplex system. We anticipate that these modern free-energy methods will be useful tools in evaluating ion transport properties of other G-quadruplex DNA channels.