Conformational diversity analysis reveals three functional mechanisms in proteins

Area of Science:

• Structural Biology
• Biophysics
• Computational Biology

Background:

• Protein dynamics are crucial for biological function.
• Previous analyses indicated a skewed distribution of protein conformational diversity, peaking at 0.5 Å C-alpha root-mean-square-deviation (RMSD).

Purpose of the Study:

• To classify proteins based on their conformational diversity and relate these classes to structure-function relationships.
• To investigate global behavior patterns within protein conformer populations.

Main Methods:

• Analysis of a curated dataset of approximately 5,000 proteins with experimentally determined conformational diversity.
• Examination of structure-based features across the conformer population for each protein.
• Identification of distinct protein classes based on RMSD distribution and associated properties.

Main Results:

• Three main protein classes were identified: 'rigid' (~60% of proteins, average RMSD = 0.83 Å) with no disordered regions, large tunnels, and small, buried cavities.
• Partially disordered proteins (average RMSD = 1.1 Å) feature disordered regions in 67% of conformers, long disordered regions, and numerous hinges.
• Malleable proteins (average RMSD = 1.3 Å) have disordered regions in 25% of conformers, flexible cavities, and the highest diversity of cognate ligands.
• Proteins within each class are largely non-homologous and lack shared fold classes or functional similarity, but share features derived from their conformer populations.

Conclusions:

• Protein conformational diversity can be categorized into distinct classes with characteristic structural and dynamic properties.
• These identified protein classes and their associated features may represent conserved conformational mechanisms underlying biological functions.
• Understanding protein dynamics through RMSD distribution provides insights into structure-function relationships.