Quantifying the protein core flexibility through analysis of cavity formation

Area of Science:

• Biophysics
• Computational Chemistry
• Materials Science

Background:

• Proteins possess heterogeneous internal structures.
• Understanding internal cavities is crucial for protein dynamics and function.
• Cavity statistics can reveal local environmental properties.

Purpose of the Study:

• To analyze cavity statistics within protein interiors and compare them to liquids.
• To investigate the relationship between cavity size distribution and local protein properties.
• To assess the flexibility of protein interiors versus liquids.

Main Methods:

• Molecular-dynamics simulations of three proteins, n-hexane, and water.
• Analysis of average cavity size, formation probability, and free energy of insertion.
• Comparison of cavity size distribution widths across different media.

Main Results:

• Protein interiors show a wide range of average cavity sizes due to heterogeneous packing.
• Cavity size distributions in proteins are unexpectedly narrow and homogeneous in width.
• Protein interiors are significantly less flexible than liquid n-hexane or water.
• Cavity distribution width correlates with experimental isothermal compressibility data.

Conclusions:

• Cavity statistics provide an efficient method to quantify local properties like packing and stiffness in heterogeneous media.
• The reduced flexibility of protein interiors is quantitatively demonstrated through cavity size distribution analysis.
• This approach offers a novel way to link microscopic cavity properties to macroscopic material characteristics.