Protein interface classification by evolutionary analysis

Abstract

BackgroundDistinguishing biologically relevant interfaces from lattice contacts in protein crystals is a fundamental problem in structural biology. Despite efforts towards the computational prediction of interface character, many issues are still unresolved.ResultsWe present here a protein-protein interface classifier that relies on evolutionary data to detect the biological character of interfaces. The classifier uses a simple geometric measure, number of core residues, and two evolutionary indicators based on the sequence entropy of homolog sequences. Both aim at detecting differential selection pressure between interface core and rim or rest of surface. The core residues, defined as fully buried residues (>95% burial), appear to be fundamental determinants of biological interfaces: their number is in itself a powerful discriminator of interface character and together with the evolutionary measures it is able to clearly distinguish evolved biological contacts from crystal ones. We demonstrate that this definition of core residues leads to distinctively better results than earlier definitions from the literature. The stringent selection and quality filtering of structural and sequence data was key to the success of the method. Most importantly we demonstrate that a more conservative selection of homolog sequences - with relatively high sequence identities to the query - is able to produce a clearer signal than previous attempts.ConclusionsAn evolutionary approach like the one presented here is key to the advancement of the field, which so far was missing an effective method exploiting the evolutionary character of protein interfaces. Its coverage and performance will only improve over time thanks to the incessant growth of sequence databases. Currently our method reaches an accuracy of 89% in classifying interfaces of the Ponstingl 2003 datasets and it lends itself to a variety of useful applications in structural biology and bioinformatics. We made the corresponding software implementation available to the community as an easy-to-use graphical web interface at http://www.eppic-web.org.

Molecular Dynamics of Major Allergens from Alternaria, Birch Pollen and Peach

“…[7] We have recently extended the oligomerization analysis to 84 allergen X-ray structures using crystal information together with a new computational tool that uses evolutionary information to address dimer formation. [8] Our study lowered the proportion of allergens with oligomeric states down to 66 % although it still seems clear that oligomerization is a common feature of allergens. [9] While most studies to derive physicochemical or structural features of allergens have focused on their 3D structure, much less attention has been paid to their dynamic properties in solution.…”

“…Since allergens induce crosslinking of IgE antibodies bound to high affinity receptors on mast cells or basophil surfaces, one would expect that an allergen dimer that triggers cross-linking should have the antigenic regions located at opposite ends on the surface. For this reason, we used a second dimer predicted by the Evolutionary Protein-Protein Interface Classifier (EPPIC) approach [8] that shows the proper orientation of epitopes (see below). A third Bet v 1 dimer corresponding to the dimeric structure of 4BK6 (cysteine at position 5) and showing proper orientation of epitopes was also utilized.…”

Determinants of Substrate Specificity in APOBEC3B

“…92 Interface surface area was calculated using the EPPIC webserver. 93 Interfaces were filtered to only show those with more than 500 A^2 of surface area. 94 Structures which have a greater number of monomers in their asymmetric unit can show the same interface multiple times, and this is counteracted by only labeling each interface once.…”

Statistical Properties of Protein-Protein Interfaces

“…The role of conserved residues in interaction surfaces has also been studied [10][11][12]. Databases have been developed with characteristics of the cyrstallographically determined interfaces [13][14][15].…”