Conformational changes in acetylcholine binding protein investigated by temperature accelerated molecular dynamics

Area of Science:

• Structural Biology
• Computational Biophysics
• Neuroscience

Background:

• Nicotinic acetylcholine receptors (nAChRs) are crucial for neurotransmission, but their gating mechanisms remain incompletely understood.
• The acetylcholine binding protein (AChBP) serves as a valuable model for the extracellular domain of nAChRs, facilitating mechanistic studies.

Purpose of the Study:

• To investigate the ligand-induced conformational changes and gating transition mechanism of AChBP using advanced simulation techniques.
• To explore the efficacy of unbiased Molecular Dynamics (MD) and Temperature Accelerated Molecular Dynamics (TAMD) in capturing these transitions.

Main Methods:

• Employed unbiased Molecular Dynamics (MD) simulations to observe stable apo and agonist-bound AChBP conformations.
• Utilized Temperature Accelerated Molecular Dynamics (TAMD) simulations to induce and accelerate the transition between apo and agonist-bound states.
• Analyzed key residue-residue interactions, particularly hydrogen bonds, to elucidate the gating mechanism.

Main Results:

• Standard MD simulations showed stable conformations, with agonist-bound structures shifting to apo upon specific sidechain modifications.
• TAMD simulations successfully induced spontaneous transitions from native conformations, accelerating the process by over tenfold compared to modified structures.
• Identified the disruption and formation of critical hydrogen bonds as the basis for the gating transition mechanism.

Conclusions:

• TAMD simulations are effective for studying the gating transition of AChBP, providing insights into nAChR mechanisms.
• The gating transition is primarily governed by the dynamics of a few key hydrogen bonds within the orthosteric cavity.
• TAMD significantly accelerates ligand dissociation, enabling the observation of complete dissociation pathways.