Looks can be deceiving: Getting misled by crystal structures - part 2

Last year we highlighted a paper that touched on some of the ways crystal structures can mislead, and a theme of FBLD 2009 was how dubious data can derail modeling efforts. Now, Jens Erik Nielsen and colleagues at University College Dublin add to the discussion by showing how the crystal lattice can potentially distort protein-ligand interactions. Their paper in J. Med. Chem. provides an analysis of the prevalence of two common structural artifacts, plus a practical tool for detecting them.

The first problem the authors consider is that some ligands make “crystal contacts.” Because a crystal is made up of a three-dimensional lattice of proteins packed together, a ligand bound near the surface of one protein may be in close contact with another protein in the crystal (a nonbiological “symmetry mate”); this contact occurs only in the context of a crystal and could distort how the ligand binds to its (true) partner protein.

The second, related problem is that water molecules that appear in the crystal structure can form bridges between a ligand and its nonbiological symmetry mate.

The authors examined a set of 1300 protein-ligand crystal structures with noncovalently bound ligands and experimentally measured binding affinities (PDBbind Database). Of these, 36% of ligands showed crystal contacts, and a similar number (37%) had crystal-related water bridges.

This doesn’t mean that all of these structures are misleading: the researchers note that “it is entirely possible that crystal contacts in some cases do not perturb the geometry of a protein-ligand complex whatsoever.” However, removing these structures before running docking experiments did improve the results.

The tricky thing about these structural artifacts is that they are often invisible, even when suspected. Most non-crystallographers focus on just on a single protein-ligand complex and don’t consider the crystal lattice when examining a crystal structure. Happily, Nielsen and colleagues have constructed a simple online tool (LIGCRYST) that can evaluate structures from the pdb to search for these types of problems. Although I’m not a crystallographer, I found it quite easy to use.

Hopefully modelers will increasingly take crystal contacts into account, and the next time you examine a structure from the pdb, you may want to give it a quick run through LIGCRYST.