The protein-folding problem: the native fold determines packing, but does packing determine the native fold?

Area of Science:

• Biochemistry
• Structural Biology
• Computational Biology

Background:

• Globular proteins spontaneously fold into specific 3D structures under physiological conditions.
• The protein-folding problem, elucidating the code dictating protein structure from amino acid sequence, remains a major challenge.
• Molecular packing and residue side-chain complementarity are hypothesized as principal determinants of native protein structure.

Purpose of the Study:

• To investigate the role of molecular packing in determining protein structure.
• To test the hypothesis that favorable side-chain interactions are key to structural specificity.
• To analyze known protein structures for evidence of preferred residue interactions.

Main Methods:

• Analysis of proteins with known three-dimensional structures.
• Examination of residue side-chain interactions within the protein interior.
• Assessment of packing densities and complementarity among amino acid residues.

Main Results:

• High packing densities, characteristic of globular proteins, are readily achieved.
• Naturally occurring hydrophobic amino acid residues exhibit favorable interactions within clusters.
• These findings suggest a simpler explanation for the high packing densities observed in proteins.

Conclusions:

• The inherent complementarity of hydrophobic amino acid residues contributes significantly to protein packing.
• This realization may simplify the approach to solving the protein-folding problem.
• Future research can leverage this understanding of hydrophobic interactions in protein structure prediction.