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Open Access Research article

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

Alexandra Shulman-Peleg1*, Maxim Shatsky4, Ruth Nussinov23 and Haim J Wolfson1*

Author Affiliations

1 School of Computer Science, Raymond and Beverly Sackler Faculty of Exact Sciences Tel Aviv University, Tel Aviv 69978, Israel

2 Physical Biosciences Division, Berkeley National Lab, California, USA

3 Basic Research Program, SAIC-Frederick, Inc. Center for Cancer Research Nanobiology Program, NCI, Frederick, MD 21702, USA

4 Department of Human Genetics and Molecular Medicine Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv 69978, Israel

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BMC Biology 2007, 5:43  doi:10.1186/1741-7007-5-43

Published: 9 October 2007



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.


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.


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.