Spatial chemical conservation of hot spot interactions in protein-protein complexes

Abstract

Background: Conservation of the spatial binding organizations at the level of physico-chemical interactions is important for the formation and stability of protein-protein complexes as well as protein and drug design. Due to the lack of computational tools for recognition of spatial patterns of interactions shared by a set of protein-protein complexes, the conservation of such interactions has not been addressed previously.

Results: We performed extensive spatial comparisons of physico-chemical interactions common to different types of protein-protein complexes. We observed that 80% of these interactions correspond to known hot spots. Moreover, we show that spatially conserved interactions allow prediction of hot spots with a success rate higher than obtained by methods based on sequence or backbone similarity. Detection of spatially conserved interaction patterns was performed by our novel MAPPIS algorithm. MAPPIS performs multiple alignments of the physico-chemical interactions and the binding properties in three dimensional space. It is independent of the overall similarity in the protein sequences, folds or amino acid identities. We present examples of interactions shared between complexes of colicins with immunity proteins, serine proteases with inhibitors and T-cell receptors with superantigens. We unravel previously overlooked similarities, such as the interactions shared by the structurally different RNase-inhibitor families.

Conclusion: The key contribution of MAPPIS is in discovering the 3D patterns of physico-chemical interactions. The detected patterns describe the conserved binding organizations that involve energetically important hot spot residues and are crucial for the protein-protein associations.

Figure 1

Shared interactions. (A) The left figure shows a PPI represented by the solvent accessible surfaces (small dots [51]) and the pseudocenters (balls). Only surface exposed pseudocenters are considered. Hydrogen bond donors are blue, acceptors – red, donors/acceptors – green, and aromatic – white. The right figure illustrates the definition of pseudocenters and the bar at the bottom illustrates the complementarity of the pseudocenter properties. (B) Alignment of 6 PPIs of serine proteases with inhibitors. The trypsins (1cbwHG, 1tawA, 1ca0HG) are gray and the subtilisins (1cseE, 2sicE, 1oyvB) are blue. The corresponding inhibitors (1cbwI, 1tawI, 1ca0I, 1cseI, 2sicI, 1oyvI) are colored ranging from yellow to purple respectively. The right figure presents the 9 spatially conserved interactions (purple arrows). The catalytic residues of the serine proteases (gray sticks) were recognized to form 5 similar interactions (3 hydrogen bonds, 1 hydrophobic aliphatic and 1 aromatic) with the corresponding hot spots of the inhibitors K15(1cbw), R15(1taw,1ca0), K45(1cse), M73(2sic) and R5(1oyv). These residues, which have different amino acid identities and backbone locations are represented as black sticks.

Figure 2

Alignment examples. (A) Alignment of 3 RNase-inhibitor PPIs. The Angiogenin is yellow (1a4yB) and the Rnase Sa (1ay7A) and barnase (1brsA) are dark and light orange. The Leucine-rich RI (1a4yA) is in magenta while the barstars (1ay7B,1brsD) are blue and purple. The rightmost figure shows the conserved interactions with the identities of the amino acids that create them in the corresponding complexes (1a4y:1ay7:1brs). The pseudocenters are represented as in Figure 1A, except the aromatic properties which are cyan. The RIs are light purple and the RNases are monochrome. (B) Alignment of 6 PPIs of E9-Im9 (1bxiAB, 1emvAB, 1fr2AB) and E7-Im7(1mz8AB, 1ujzAB, 1fr2AB). The E9 are cyan and the E7 are blue. The Im9 and Im7 are yellow and red respectively. The right figure details the 7 conserved interactions labeled by the amino acids of 1bxiAB.

Figure 3

Overview of the MAPPIS method.