Many proteins use a long channel to guide the substrate or ligand molecules into the well-defined active sites for catalytic reactions or for switching molecular states. Specific substrates of membrane transporters can migrate to another side of cellular compartment. SLITHER is a web server that can generate contiguous conformations of a molecule along a curved tunnel inside a protein, and the binding free energy profile along the predicted channel pathway. SLITHER adopts an iterative docking scheme, which combines with a puddle-skimming procedure, i.e., repeatedly elevating the potential energies of the identified global minima, thereby determines the contiguous binding modes of substrates inside the protein. In contrast to the HOLE program that is widely used to determine the geometric dimensions in the ion channels, SLITHER can be applied to predict whether a substrate molecule can crawl through an inner channel or a half-channel of proteins across surmountable energy barriers.

Reference:
Po-Hsien Lee, Kuei-Ling Kuo, Pei-Ying Chu, Eric M. Liu, Jung-Hsin Lin*. SLITHER: a web server for generating contiguous conformations of substrate molecules entering into deep active sites of proteins or migrating through channels in membrane transporters. Nucleic Acids Research 37: W559-W564 (2009)

(a)	(b)
Figure 1: (a) Geometry of the internal channel of glucose transporter I (PDB ID: 1SUK) depicted by HOLE. (b) A series of contiguous conformations generated by SLITHER.