Accurate Methyl Group Dynamics in Protein Simulations with AMBER Force Fields

Area of Science:

• Biophysics
• Computational Chemistry
• Structural Biology

Background:

• Nuclear Magnetic Resonance (NMR) spin relaxation measurements provide insights into protein dynamics.
• Accurate simulation of methyl group rotation is essential for interpreting NMR data.
• Existing methods often rely on NMR information or system-specific parameters.

Purpose of the Study:

• To develop and validate an all-atom molecular dynamics (MD) simulation approach for directly simulating methyl group dynamics in proteins.
• To enable direct comparison between MD simulations and NMR spin relaxation measurements without simplified motional models.

Main Methods:

• Calculation of time-correlation functions (TCFs) for C-H bonds in methyl groups.
• Explicit consideration of TCF truncation due to molecular tumbling.
• Reparameterization of methyl group rotation potential energy barriers using coupled cluster calculations.
• Utilizing the TIP4P/2005 solvation model.

Main Results:

• Accurate simulation of methyl group dynamics requires reparametrization of the AMBER ff99SB*-ILDN force field.
• The TIP4P/2005 solvation model provides tumbling correlation times consistent with experimental data.
• Methyl axis order parameters and correlation times align well with NMR deuterium relaxation experiments.
• MD-derived relaxation rates and spectral densities closely match NMR data.

Conclusions:

• The presented MD approach accurately simulates methyl group dynamics accessible via NMR.
• The method validates the reparameterized force field and solvation model for protein dynamics studies.
• This work facilitates a direct, assumption-free comparison between MD simulations and NMR relaxation data.