Are crystallographic B-factors suitable for calculating protein conformational entropy?

Area of Science:

• Structural biology
• Biophysics
• Computational chemistry

Background:

• Conformational entropy is crucial for understanding protein-ligand and protein-protein interactions.
• Experimental methods for measuring protein conformational entropy are limited.
• Molecular dynamics (MD) simulations are commonly used but face convergence and accuracy challenges.

Purpose of the Study:

• To evaluate the reliability of crystallographic B-factors for estimating protein conformational entropies.
• To compare B-factor derived entropies with experimental NMR data and MD simulation results.

Main Methods:

• Analysis of B-factors (atomic displacement parameters) from protein crystal structures.
• Comparison with entropies derived from NMR relaxation experiments.
• Comparison with entropies obtained from molecular dynamics simulations (in solution and crystal).
• Application of translation-libration-screw refinement and MD-based correlated motion descriptions.
• Analysis of entropy changes upon ligand binding.

Main Results:

• B-factor derived conformational entropies are unreliable.
• B-factors include global protein motion and exclude correlated movements.
• Contributions from static disorder and model errors affect B-factor accuracy.
• B-factor precision is insufficient for reliable entropy estimation.
• B-factor derived fluctuations are incompatible with MD simulation results.

Conclusions:

• Crystallographic B-factors are not a reliable source for calculating protein conformational entropies.
• Limitations include global motion, lack of correlated motion, and other confounding factors.
• Further methodological development is needed for accurate entropy determination from structural data.