Protein structural alignment: a bit of control with LOVOAlign

The Different Aims of Structural Alignment

Several weeks ago I posted a series of pieces about protein structural alignment tools (see Gerald Lushington Tumblr Blog for the last of the posts) that were geared toward perceiving pharmacophorically similar binding sites across different targets.  My underlying aim in promoting these tools was to emphasize that these correspond to a somewhat newer class of protein alignment tools, relative to the original batch which were primarily focused on superimposing structures according to holistic properties such as conserved folds and domains.  In truth, there are still other reasons why one might want to do some sort of protein structural alignment.  I would encourage readers to suggest those that might occur to them, but the one that I recently grappled with had to do with predicting protein-protein interaction complexes.

The most commonly used computational tools for predicting how multiple proteins associate with each other are:

1. homology modeling:  if someone has crystallized a bound complex of proteins A and B, and you want to predict how A and C will bind, you could use any sequence homology between B and C to align C to the position / orientation / conformation of the complexed B structure
2. protein docking:  if there isn't a viable template for a bound AB complex, you can systematically sample the translational and rotational coordinates of C within the region of A to see what orientation would produce the best steric and electrostatic complementarity between A and C.

While the above pair of methods might seem to provide reasonable coverage of different possible modeling scenarios, there is a distinct opportunity that neither are well suited to exploit:  there are numerous crystal structures that span more than one bound protein but large fractions of one or more of those proteins has not been resolved.  Another related scenario is where you have a relatively complete structure of A bound to B, but B is much smaller than C, or only a portion of B near the interaction surface is structurally related to C.  In such a case, homology modeling may fail because the structures B and C are too different to support accurate comparative analysis.  Docking simulations might work, but there is no guarantee they would behave any more reliably than average (which is in general fairly sketchy).  The answer of course is not too outrageous:  a computer program that seeks only to align a user-defined subset of C's structure to a subset of B.  This is one of the potentially very useful services that LOVOAlign can accomplish.  In addition to being fairly easy to use, the program is fast and capable of a broad range of other protein-protein alignment tasks (including the aforementioned goal of pharmacophore alignment.  And better yet, LOVOAlign is available for free and is provided with open source access.



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Posts in this blog represent the honest opinions of Gerald Lushington (click here for CV) and have not been affected by commercial interests or other inducements.