Comparing multislice projections of MD simulations with cryo-EM exposes structural prediction errors.

Area of Science:

• Structural biology
• Biophysics
• Computational chemistry

Background:

• Cryo-electron microscopy (cryoEM) determines atomic structures, while molecular dynamics (MD) simulations predict molecular motion.
• Integrating cryoEM and MD is crucial for understanding biomolecular dynamics, but direct evaluation of MD predictions remains challenging.

Purpose of the Study:

• To develop and apply a method for directly comparing MD simulations with cryoEM data.
• To assess the accuracy of MD simulations in predicting membrane structure and dynamics as observed by cryoEM.

Main Methods:

• Utilized multislice wave propagation to project MD trajectory snapshots (Coarse-Grained and All-Atom) into simulated cryoEM 3D reconstructions.
• Compared simulated cryoEM images with experimental data for membranes with varying curvature and lipid compositions.

Main Results:

• MD simulations qualitatively captured membrane fluidity and contrast observed in cryoEM.
• MD simulations accurately predicted bilayer dimensions for simple, flat lipid bilayers.
• Martini3 Coarse-Grained MD simulations inaccurately predicted membrane thickness changes in high-curvature and heterogeneous lipid environments, particularly due to issues with polyunsaturated lipids and cholesterol.

Conclusions:

• Direct comparison of simulated and experimental cryoEM images is a viable method for evaluating MD predictions.
• Current MD force fields, specifically Martini3, require improvement for accurately simulating complex membrane behaviors.
• Refining MD force fields based on cryoEM data will enhance the predictive power of simulations for membrane biophysics and structural biology.