SLITHER

SLITHER generates contiguous conformations of substrates and ligands traversing curved tunnels in proteins and computes binding free energy profiles along these pathways.

Key Features:

• Iterative Docking Scheme: Employs an iterative docking approach combined with a puddle-skimming procedure that repeatedly elevates potential energies at identified global minima to determine contiguous substrate binding modes.
• Energy Barrier Prediction: Predicts whether a substrate molecule can traverse inner or half-channels by evaluating energy barriers rather than relying solely on geometric dimensions.
• Pore-Facing Residues Identification: Provides a list of pore-facing residues along the channel pathway for comparison with genetic disease–associated mutations.
• Fragment-Based Drug Design Support: Determines adjacent binding poses within protein channels to support fragment-based drug design targeting channel binding sites.

Scientific Applications:

• Substrate and Ligand Transport Analysis: Facilitates study of transport through membrane transporters and enzymes with long channels that guide molecules to active sites.
• Catalysis and Conformational State Analysis: Uses binding free energy profiles and contiguous conformations to investigate catalytic processes and molecular state transitions.
• Drug Design and Mutation Impact Assessment: Supports fragment-based drug design and assessment of the functional impact of channel-lining mutations linked to disease.

Methodology:

Applies an iterative docking scheme with a puddle-skimming procedure that elevates potential energies at identified global minima to generate contiguous conformations and calculate binding free energy profiles along protein tunnels.