Why not consider a spherical protein? Implications of backbone hydrogen bonding for protein structure and function

Area of Science:

• Structural Biology
• Computational Biology
• Biophysics

Background:

• Understanding the fundamental principles governing protein structure and function is crucial in molecular biology.
• The role of evolution versus intrinsic physical properties in shaping protein capabilities remains an area of active research.

Purpose of the Study:

• To investigate the intrinsic geometric properties of protein structures that enable molecular function without evolutionary selection.
• To compare real protein structures with computationally generated models to identify key structural determinants of function.

Main Methods:

• Analysis of real, single-domain protein structures.
• Generation and analysis of computationally designed homopolypeptides and artificial protein-like structures.
• Generation and analysis of quasi-spherical random proteins lacking secondary structure.

Main Results:

• Artificial structures, without evolution, exhibited similar backbone hydrogen bonding, global shape, and structural matches to real proteins.
• These artificial structures possessed native-like ligand binding cavities and interfaces for protein-protein and DNA interactions.
• Quasi-spherical random proteins, lacking secondary structure, showed protein-like bond angle distributions and structural matches, suggesting compactness and local stiffness are key.

Conclusions:

• Protein structure possesses inherent capabilities for molecular function, driven by local chain stiffness and compactness.
• The packing of secondary structural elements is critical for generating geometries required for intermolecular binding.
• Backbone hydrogen bonding significantly contributes to both protein structure and function, providing a basis for evolutionary selection.