From Atoms to Neuronal Spikes: A Multiscale Simulation Framework

Area of Science:

• Computational neuroscience
• Molecular biophysics
• Pharmacology

Background:

• Understanding ion channel function is crucial for elucidating neurological diseases and designing drugs.
• Current models often lack the integration of molecular-level changes with neuronal network behavior.

Purpose of the Study:

• To develop and validate a multiscale simulation framework connecting molecular and neuronal simulations.
• To predict the impact of ion channel variations on neuronal excitability and membrane potential dynamics.

Main Methods:

• Coupling molecular dynamics (MD) simulations of AMPA receptors (AMPARs) with detailed neuronal models (Arbor framework).
• Integrating coarse-grained Monte Carlo gating simulations of voltage-gated ion channels with Arbor models for bidirectional feedback.
• Investigating the influence of lipid membrane composition on ion channel gating.

Main Results:

• MD simulations revealed altered current and conductance in disease-associated AMPAR variants, impacting neuronal excitability.
• Bidirectional coupling between ion channel states and membrane potential was established, consistent with electrophysiological recordings.
• The study demonstrated the framework's ability to link atomistic perturbations to macroscopic neuronal function.

Conclusions:

• The proposed multiscale simulation approach effectively links molecular events to neuronal excitability.
• This framework provides a powerful tool for studying neurological disease mechanisms and guiding neuroactive drug discovery.
• The inclusion of lipid membrane effects offers a more comprehensive understanding of ion channel behavior.