Microsecond time-scale conformational exchange in proteins: using long molecular dynamics trajectory to simulate NMR...

Area of Science:

• Biophysics
• Computational Chemistry
• Structural Biology

Background:

• Ultra-long molecular dynamics (MD) simulations enable modeling of microsecond protein dynamics.
• NMR relaxation dispersion measurements probe exchange broadening effects (R(ex)).
• Identifying exchanging species and complex exchange networks is crucial for understanding protein dynamics.

Purpose of the Study:

• To simulate protein dynamics and predict NMR relaxation dispersion measurements using MD.
• To investigate the source of exchange broadening in protein BPTI.
• To validate the utility of long MD simulations for studying protein dynamics.

Main Methods:

• Utilized a millisecond-long MD trajectory of protein BPTI.
• Simulated the time variation of amide (15)N chemical shifts.
• Predicted (15)N line exchange broadening and relaxation dispersion outcomes.

Main Results:

• Simulated exchange broadening effects consistent with experimental findings.
• Identified fast (~10-100 μs) isomerization of the C14-C38 disulfide bond as the cause of R(ex).
• Demonstrated the capability of MD simulations to predict NMR relaxation dispersion measurements.

Conclusions:

• Long MD simulations are powerful tools for studying protein dynamics and NMR relaxation dispersion.
• Disulfide bond isomerization is a key dynamic process influencing NMR observables.
• This approach aids in identifying excited states and mapping complex exchange networks.