Molecular Dynamics Simulations Provide Atomistic Insight into Hydrogen Exchange Mass Spectrometry Experiments

Area of Science:

• Biochemistry and Biophysics
• Computational Biology
• Structural Biology

Background:

• Proteins are dynamic entities, existing in multiple conformations essential for their function.
• Hydrogen/Deuterium Exchange Mass Spectrometry (HX/MS) is crucial for studying protein dynamics, but data interpretation is challenging.
• ERK2MAPK, a key signaling protein, has been studied using HX/MS to understand its conformational plasticity.

Purpose of the Study:

• To develop a theoretical framework using all atom Molecular Dynamics (MD) simulations for interpreting HX/MS data.
• To provide atomic-level insights into protein dynamics and conformational ensembles.
• To rationalize experimentally observed changes in protein dynamics at the residue level.

Main Methods:

• All atom Molecular Dynamics (MD) simulations.
• Detailed analysis of protein-solvent interactions from MD trajectories.
• Integration of MD simulations with Hydrogen/Deuterium Exchange Mass Spectrometry (HX/MS) data.

Main Results:

• MD simulations accurately predict proton exchange for peptides in HX/MS experiments.
• The study rationalizes residue-level changes in HX/MS exchange rates under different conditions.
• Functional dynamics of ERK2MAPK are largely explained by its native state conformational ensemble.

Conclusions:

• Combining HX/MS with all atom MD simulations offers a powerful method for studying protein dynamics.
• This integrated approach provides atomic resolution understanding of protein native state dynamics.
• The findings facilitate a deeper comprehension of how protein flexibility relates to function.