Ringer

Ringer detects alternate protein conformations by systematically sampling electron density around protein side-chain dihedral angles in X-ray electron density maps to uncover lowly populated rotamers.

Key Features:

• Systematic dihedral sampling: Samples electron density around side-chain dihedral angles to reveal alternate rotamers.
• Detection of weak features: Identifies weak, nonrandom electron-density peaks indicative of low-occupancy alternate conformations.
• Statistical validation: Reports statistical significance for detected peaks with values as low as P < 10^(-5).
• Model-bias-free analysis: Analyzes accurate electron density maps devoid of model bias to confirm weak densities.
• Sensitivity below conventional cutoff: Extends signal detection below the conventional 1 sigma cutoff used in electron density maps.
• Large-scale demonstration: Applied across a dataset of 402 protein structures.
• Linkage to functional states: Enables correlation of detected alternate conformations with ligand interactions and ensemble shifts.

Scientific Applications:

• Ensemble analysis: Reveals shifts in structural ensembles that reflect alternative conformational states.
• Ligand recognition studies: Connects alternate rotamers to ligand recognition and binding-site variability.
• Protein function and folding: Elucidates mechanisms of protein folding and function that depend on conformational flexibility.
• Structural case study — calmodulin: Applied to high-resolution free and peptide-bound calmodulin structures to show alternate conformations integral to ligand interaction.
• Structure-based design: Informs structural biology and drug design by identifying dynamic conformational states within binding sites.

Methodology:

Systematic sampling of electron densities around side-chain dihedral angles across 402 protein structures, analysis of electron density maps devoid of model bias, statistical evaluation of peaks (P < 10^(-5)), and detection of signal below the conventional 1 sigma cutoff.