10.1021/ct400198q.s001
Liaoran Cao
Liaoran
Cao
Chao Lv
Chao
Lv
Wei Yang
Wei
Yang
Hidden Conformation Events in DNA Base Extrusions:
A Generalized-Ensemble Path Optimization and Equilibrium Simulation
Study
American Chemical Society
2016
rotation
pathway
MFEP result
transition state
opening
DNA Base Extrusions
sampling
OTPRW
dynamic
Equilibrium Simulation StudyDNA base extrusion
TS
analysis
portion
2016-02-19 01:18:48
Media
https://acs.figshare.com/articles/media/Hidden_Conformation_Events_in_DNA_Base_Extrusions_A_Generalized_Ensemble_Path_Optimization_and_Equilibrium_Simulation_Study/2387968
DNA
base extrusion is a crucial component of many biomolecular
processes. Elucidating how bases are selectively extruded from the
interiors of double-strand DNAs is pivotal to accurately understanding
and efficiently sampling this general type of conformational transitions.
In this work, the on-the-path random walk (OTPRW) method, which is
the first generalized-ensemble sampling scheme designed for finite-temperature-string
path optimizations, was improved and applied to obtain the minimum
free-energy path (MFEP) and the free-energy profile of a classical
B-DNA major-groove base-extrusion pathway. Along the MFEP, an intermediate
state and the corresponding transition state were located and characterized.
The MFEP result suggests that a base-plane-elongation event rather
than the commonly focused base-flipping event is dominant in the transition-state
(TS) formation portion of the pathway; and the energetic penalty at
the transition state is mainly introduced by the stretching of the
Watson–Crick base pair. Moreover, to facilitate the essential
base-plane-elongation dynamics, the surrounding environment of the
flipped base must be intimately involved. Further taking advantage
of the extended-dynamics nature of the OTPRW Hamiltonian, an equilibrium
generalized ensemble simulation was performed along the optimized
path; based on the collected samples, several base-flipping (opening)
angle collective variables were evaluated. In correspondence with
the MFEP result, the collective variable analysis result reveals that
none of these commonly employed flipping (opening) angles alone can
adequately represent the base-extrusion pathway, especially in the
pre-TS portion. As further revealed by the collective variable analysis,
the base-pairing partner of the extrusion target undergoes a series
of in-plane rotations to facilitate the base-plane-elongation dynamics.
A base-plane rotation angle is identified to be a possible reaction
coordinate to represent these in-plane rotations. Notably, these in-plane
rotation motions may play a pivotal role in determining the base-extrusion
selectivity.