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Download fileNudged Elastic Band Study on the N‑Terminal Domain Conformational Pathways of Annexin A1 from a Buried State to an Exposed State
journal contribution
posted on 2019-11-21, 18:43 authored by Kimberly Lewis, Samuel Lindsay, Yumin LiMapping the conformational pathway of biomolecules is
a great challenge because of the large size and complexity of biomolecules.
The nudged elastic band (NEB) method has been applied to study the
reaction pathways for both small organic molecules and small peptides
of a few amino acids. In this work, for the first time, the NEB method
was employed to study the conformational pathways of Annexin A1, a
membrane-binding protein of 334 amino acids. The N-terminal domain
conformational change from the buried state within the core domain
to the exposed state outside the core domain is a vital step for Annexin
A1 to interact with membranes or target proteins. In this work, multiple
molecular dynamics simulations using the NEB method were performed
to simulate the N-terminal domain conformational pathway of Annexin
A1. Our results suggested that the N-terminal domain of Annexin A1
is removed from the repeat III of the core domain in a sliding motion.
The loop region of repeat III covering the N-terminal helix in the
buried state does not lift up for the N-terminal to swing out of the
pocket; instead, the N-terminal pulls out from the bottom of the core
domain. The N-terminal domain linker region (S27–N42) flexibility
is critical for the N-terminal domain conformational changes. Our
results also suggested a two-step folding process for the helix D
in repeat III, M247–V250 folds first followed by the folding
of L251–E254. The results demonstrated that the NEB method
could be an effective tool for theoretical studies on conformational
pathways of biomolecules.