Sub-Atomic Resolution Crystal Structures Reveal Conserved Geometric Outliers at Functional Sites

Area of Science:

• Biochemistry
• Structural Biology
• Neuroscience

Background:

• Myelin protein 2 (P2) is a key peripheral membrane protein in the vertebrate nervous system's myelin sheath.
• P2 is implicated in lipid transport and the structural organization of the myelin membrane.

Purpose of the Study:

• To refine the crystal structure of human P2 at ultrahigh resolution.
• To investigate the role of unconventional amino acid conformations and hydrogen bonding in P2 structure and function.

Main Methods:

• Extended crystallographic studies on human P2.
• Refinement of crystal structures at ultrahigh resolutions (0.72 Å for perdeuterated, 0.86 Å for hydrogenated forms).
• Analysis of hydrogen bond patterns and amino acid residue conformations.

Main Results:

• Observed characteristic differences in C-H…O hydrogen bond patterns between different secondary structures.
• Identified unconventional conformations, including bent aromatic rings, twisted guanidinium groups, and non-planar peptide bonds.
• Found clusters of non-ideal conformations indicating local functional strain, consistent with other protein families like SH3 and FABP.

Conclusions:

• Ultrahigh-resolution data reveal real geometric outliers in protein structures that are likely relevant to biological function, such as ligand binding and conformational changes.
• Deuteration of protein and/or solvent are effective variables for optimizing protein crystal structures.
• The study provides a high-resolution view of strained amino acid conformations in P2, potentially critical for its role in myelin.