‘Double water exclusion’: a hypothesis refining the O-ring theory for the hot spots at protein interfaces

Motivation: The O-ring theory reveals that the binding hot spot at a protein interface is surrounded by a ring of residues that are energetically less important than the residues in the hot spot. As this ring of residues is served to occlude water molecules from the hot spot, the O-ring theory is also called ‘water exclusion’ hypothesis. We propose a ‘double water exclusion’ hypothesis to refine the O-ring theory by assuming the hot spot itself is water-free. To computationally model a water-free hot spot, we use a biclique pattern that is defined as two maximal groups of residues from two chains in a protein complex holding the property that every residue contacts with all residues in the other group

Protein binding hot spots and the residue-residue pairing preference: a water exclusion perspective

<p>Abstract</p> <p>Background</p> <p>A protein binding hot spot is a small cluster of residues tightly packed at the center of the interface between two interacting proteins. Though a hot spot constitutes a small fraction of the interface, it is vital to the stability of protein complexes. Recently, there are a series of hypotheses proposed to characterize binding hot spots, including the pioneering O-ring theory, the insightful 'coupling' and 'hot region' principle, and our 'double water exclusion' (DWE) hypothesis. As the perspective changes from the O-ring theory to the DWE hypothesis, we examine the physicochemical properties of the binding hot spots under the new hypothesis and compare with those under the O-ring theory.</p> <p>Results</p> <p>The requirements for a cluster of residues to form a hot spot under the DWE hypothesis can be mathematically satisfied by a biclique subgraph if a vertex is used to represent a residue, an edge to indicate a close distance between two residues, and a bipartite graph to represent a pair of interacting proteins. We term these hot spots as DWE bicliques. We identified DWE bicliques from crystal packing contacts, obligate and non-obligate interactions. Our comparative study revealed that there are abundant <it>unique </it>bicliques to the biological interactions, indicating specific biological binding behaviors in contrast to crystal packing. The two sub-types of biological interactions also have their own signature bicliques. In our analysis on residue compositions and residue pairing preferences in DWE bicliques, the focus was on interaction-preferred residues (ipRs) and interaction-preferred residue pairs (ipRPs). It is observed that hydrophobic residues are heavily involved in the ipRs and ipRPs of the obligate interactions; and that aromatic residues are in favor in the ipRs and ipRPs of the biological interactions, especially in those of the non-obligate interactions. In contrast, the ipRs and ipRPs in crystal packing are dominated by hydrophilic residues, and most of the anti-ipRs of crystal packing are the ipRs of the obligate or non-obligate interactions.</p> <p>Conclusions</p> <p>These ipRs and ipRPs in our DWE bicliques describe a diverse binding features among the three types of interactions. They also highlight the specific binding behaviors of the biological interactions, sharply differing from the artifact interfaces in the crystal packing. It can be noted that DWE bicliques, especially the unique bicliques, can capture deep insights into the binding characteristics of protein interfaces.</p

Interacting amino acid preferences of 3D pattern pairs at the binding sites of transient and obligate protein complexes

To assess the physico-chemical characteristics of protein-protein interactions, protein sequences and overall structural folds have been analyzed previously. To highlight this, discovery and examination of amino acid patterns at the binding sites defined by structural proximity in 3-dimensional (3D) space are essential. In this paper, we investigate the interacting preferences of 3D pattern pairs discovered separately in transient and obligate protein complexes. These 3D pattern pairs are not necessarily sequence-consecutive, but each residue in two groups of amino acids from two proteins in a complex is within certain &deg;A threshold to most residues in the other group. We develop an algorithm called AA-pairs by which every pair of interacting proteins is represented as a bipartite graph, and it discovers all maximal quasi-bicliques from every bipartite graph to form our 3D pattern pairs. From 112 and 2533 highly conserved 3D pattern pairs discovered in the transient and obligate complexes respectively, we observe that Ala and Leu is the highest occuring amino acid in interacting 3D patterns of transient (20.91%) and obligate (33.82%) complexes respectively. From the study on the dipeptide composition on each side of interacting 3D pattern pairs, dipeptides Ala-Ala and Ala-Leu are popular in 3D patterns of both transient and obligate complexes. The interactions between amino acids with large hydrophobicity difference are present more in the transient than in the obligate complexes. On contrary, in obligate complexes, interactions between hydrophobic residues account for the top 5 most occuring amino acid pairings.<br /