Dataset Information

Integrating water exclusion theory into ? contacts to predict binding free energy changes and binding hot spots.

ABSTRACT:

Background

Binding free energy and binding hot spots at protein-protein interfaces are two important research areas for understanding protein interactions. Computational methods have been developed previously for accurate prediction of binding free energy change upon mutation for interfacial residues. However, a large number of interrupted and unimportant atomic contacts are used in the training phase which caused accuracy loss.

Results

This work proposes a new method, ?ACVASA, to predict the change of binding free energy after alanine mutations. ?ACVASA integrates accessible surface area (ASA) and our newly defined ? contacts together into an atomic contact vector (ACV). A ? contact between two atoms is a direct contact without being interrupted by any other atom between them. A ? contact's potential contribution to protein binding is also supposed to be inversely proportional to its ASA to follow the water exclusion hypothesis of binding hot spots. Tested on a dataset of 396 alanine mutations, our method is found to be superior in classification performance to many other methods, including Robetta, FoldX, HotPOINT, an ACV method of ? contacts without ASA integration, and ACVASA methods (similar to ?ACVASA but based on distance-cutoff contacts). Based on our data analysis and results, we can draw conclusions that: (i) our method is powerful in the prediction of binding free energy change after alanine mutation; (ii) ? contacts are better than distance-cutoff contacts for modeling the well-organized protein-binding interfaces; (iii) ? contacts usually are only a small fraction number of the distance-based contacts; and (iv) water exclusion is a necessary condition for a residue to become a binding hot spot.

Conclusions

?ACVASA is designed using the advantages of both ? contacts and water exclusion. It is an excellent tool to predict binding free energy changes and binding hot spots after alanine mutation.

SUBMITTER: Liu Q

PROVIDER: S-EPMC3941611 | biostudies-literature | 2014 Feb

REPOSITORIES: biostudies-literature

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Publications

Integrating water exclusion theory into β contacts to predict binding free energy changes and binding hot spots.

Liu Qian Q Hoi Steven C H SC Kwoh Chee Keong CK Wong Limsoon L Li Jinyan J

BMC bioinformatics 20140226

<h4>Background</h4>Binding free energy and binding hot spots at protein-protein interfaces are two important research areas for understanding protein interactions. Computational methods have been developed previously for accurate prediction of binding free energy change upon mutation for interfacial residues. However, a large number of interrupted and unimportant atomic contacts are used in the training phase which caused accuracy loss.<h4>Results</h4>This work proposes a new method, βACVASA, to ...[more]

PMID: 24568581

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Project description:BackgroundA 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.ResultsThe 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 unique 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.ConclusionsThese 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.