Polarity as a criterion in protein design

Area of Science:

• Biochemistry
• Computational Biology
• Structural Biology

Background:

• Assessing the validity of designed protein structures is crucial for advancing protein engineering and drug discovery.
• Distinguishing natural, correctly folded globular proteins from misfolded or hypothetical structures requires reliable computational metrics.

Purpose of the Study:

• To develop and validate computational criteria for evaluating designed protein structures.
• To identify characteristic quantities of globular proteins that can serve as benchmarks for assessing protein design quality.

Main Methods:

• Empirical analysis of exposed and buried side-chain surfaces in 128 known globular proteins.
• Derivation of characteristic quantities, specifically polar fractions of surface and interior side chains.
• Application of these criteria to screen seven hypothetical protein structures and one designed nutritional protein.

Main Results:

• The polar fraction of side chains on the protein surface and in the interior are key distinguishing features of globular proteins.
• Three of seven tested hypothetical structures were rejected due to deviations in polar side-chain distribution.
• A designed nutritional protein exhibited characteristics significantly different from typical globular proteins.

Conclusions:

• Database-derived characteristic quantities provide a robust method for computationally screening designed proteins.
• These metrics can aid in identifying potential errors in experimentally determined protein structures (X-ray, NMR).
• The developed test enhances the reliability of protein design and structural analysis prior to experimental validation.