LifeSoaks: a tool for analyzing solvent channels in protein crystals and obstacles for soaking experiments

Area of Science:

• Structural biology
• Biophysics
• Computational chemistry

Background:

• Protein crystal structures contain solvent-filled spaces enabling molecular mobility.
• Understanding solvent channel geometry is vital for studying intracrystalline dynamics.
• Ligand diffusion through crystal channels is critical for structure-based drug design.

Purpose of the Study:

• Introduce LifeSoaks, a novel computational tool for analyzing and visualizing solvent channels in protein crystals.
• Assess the impact of solvent channel geometry and bottlenecks on ligand diffusion in protein crystals.
• Provide insights into optimizing soaking experiments for structure-based drug design.

Main Methods:

• Developed LifeSoaks utilizing a Voronoi diagram-based periodic channel representation.
• Efficiently computed channel geometry and identified bottleneck locations and sizes.
• Analyzed bottleneck radii for all Protein Data Bank (PDB) crystal structures.
• Examined a curated dataset of structures from soaking experiments.

Main Results:

• LifeSoaks provides an efficient method for representing and analyzing solvent channels.
• Bottleneck radii, indicative of diffusion hindrance, can be directly derived from the channel representation.
• Calculated bottleneck radii for all PDB structures and analyzed experimental data.
• Results suggest bottleneck size and channel visualization aid in planning soaking experiments.

Conclusions:

• LifeSoaks is a valuable tool for understanding solvent channel dynamics in protein crystals.
• Consideration of bottleneck radii and visual inspection of channels can improve soaking experiment success rates.
• This approach aids in rationalizing and optimizing drug design strategies involving ligandSoaking.