Vibrational entropy of a protein: large differences between distinct conformations

Area of Science:

• Computational biophysics
• Protein dynamics
• Thermodynamics

Background:

• Vibrational entropy (VE) is a major configurational entropy contribution in globular proteins.
• VE is often neglected in calculations due to complexity and the belief that it's similar across well-packed conformations.
• Accurate estimation of VE is vital for understanding protein equilibrium properties.

Purpose of the Study:

• To investigate the significance of vibrational entropy (VE) in globular protein free energy at ambient conditions.
• To explicitly measure VE for different protein conformations using simulation data.
• To evaluate new coordinate sets for improved VE estimation.

Main Methods:

• Employed the quasi-harmonic approximation to estimate VE.
• Utilized three coordinate sets: Cartesian, bond-angle-torsion (BAT), and a novel rotamer-degeneracy lifted BAT coordinates.
• Analyzed simulation data from a test protein across six distinct conformations.

Main Results:

• Obtained VE estimates that were dependent on the coordinate set used.
• Discovered significant VE differences (comparable to overall protein stability) among the studied conformations.
• The new rotamer-degeneracy lifted BAT coordinates provided improved VE estimates by addressing limitations of the quasi-harmonic approximation.

Conclusions:

• Vibrational entropy is a critical factor in protein free energy, with conformation-dependent variations.
• The choice of coordinate system significantly influences VE calculations.
• These findings have substantial implications for computational methods in protein structure prediction, design, and NMR refinement.