Anatomy of hot spots in protein interfaces

Bogan, Andrew A.; Thorn, Kurt S.

doi:10.1006/jmbi.1998.1843

Cited by 1,830 publications

(2,131 citation statements)

References 64 publications

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“…They are underrepresented by the aliphatic hydrophobic amino acids, with a significant depletion of valine (P < 0.005; G-test subject to the FDR correction). These findings are supported by previous reports (Bogan and Thorn, 1998;Jackson, 1999) claiming that tyrosine, tryptophan and charged residues, are generally preferred in protein-protein interfaces due to their capability to form a multitude of interactions.…”

Section: Amino Acid Preference Of Epitopessupporting

confidence: 88%

“…Comparison between epitopes and other types of proteinprotein interfaces in transient hetero-complexes with respect to physico-chemical and structural characteristics (Bogan and Thorn, 1998;Jones and Thornton, 1995, 1996, 1997aNeuvirth et al, 2004), revealed general similarities between the two types of protein regions. Namely, preference for tyrosine and tryptophan residue and unorganized secondary structures was found to characterize both types of interactions.…”

Section: Discussionmentioning

confidence: 99%

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Computational characterization of B-cell epitopes

Rubinstein

Mayrose

Halperin

et al. 2008

Molecular Immunology

219

233

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Characterizing B-cell epitopes is a fundamental step for understanding the immunological basis of bio-recognition. To date, epitope analyses have either been based on limited structural data, or sequence data alone. In this study, our null hypothesis was that the surface of the antigen is homogeneously antigenic. To test this hypothesis, a large dataset of antibody-antigen complex structures, together with crystal structures of the native antigens, has been compiled. Computational methods were developed and applied to detect and extract physico-chemical, structural, and geometrical properties that may distinguish an epitope from the remaining antigen surface. Rigorous statistical inference was able to clearly reject the null hypothesis showing that epitopes are distinguished from the remaining antigen surface in properties such as amino acid preference, secondary structure composition, geometrical shape, and evolutionary conservation. Specifically, epitopes were found to be significantly enriched with tyrosine and tryptophan, and to show a general preference for charged and polar amino acids. Additionally, epitopes were found to show clear preference for residing on planar parts of the antigen that protrude from the surface, yet with a rugged surface shape at the atom level. The effects of complex formation on the structural properties of the antigen were also computationally characterized and it is shown that epitopes undergo compression upon antibody binding. This correlates with the finding that epitopes are enriched with unorganized secondary structure elements that render them flexible. Thus, this study extends the understanding of the underlying processes required for antibody binding, and reveals new aspects of the antibody-antigen interaction.

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Section: Amino Acid Preference Of Epitopessupporting

confidence: 88%

Section: Discussionmentioning

confidence: 99%

Computational characterization of B-cell epitopes

Rubinstein

Mayrose

Halperin

et al. 2008

Molecular Immunology

219

233

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show abstract

“…Interface cores are enriched in aromatic and aliphatic residues and depleted in the charged residues Lys, Glu and Asp, but not Arg. Moreover, interface core residues are better conserved in evolution than the rest of the protein surface (Guharoy & Chakrabarti, 2005) and they constitute the majority of the 'hot spots' which strongly destabilize the assembly when substituted by mutation (Covell & Wallqvist, 1997;Bogan & Thorn, 1998;Guerois et al, 2002;Kortemme & Baker, 2002). Thus, interface cores resemble the protein interior except for the presence of Arg residues, which are as abundant at protein-protein interfaces, even in the core, as elsewhere on the protein surface.…”

Section: Permanent Assemblies Versus Transient Complexes: Interface Smentioning

confidence: 99%

Macromolecular recognition in the Protein Data Bank

Janin

Rodier

Chakrabarti

et al. 2006

Acta Crystallogr D Biol Cryst

101

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Crystal structures deposited in the Protein Data Bank illustrate the diversity of biological macromolecular recognition: transient interactions in protein-protein and protein-DNA complexes and permanent assemblies in homodimeric proteins. The geometric and physical chemical properties of the macromolecular interfaces that may govern the stability and specificity of recognition are explored in complexes and homodimers compared with crystal-packing interactions. It is found that crystal-packing interfaces are usually much smaller; they bury fewer atoms and are less tightly packed than in specific assemblies. Standard-size interfaces burying 1200-2000 Å 2 of protein surface occur in protease-inhibitor and antigen-antibody complexes that assemble with little or no conformation changes. Short-lived electron-transfer complexes have small interfaces; the larger size of the interfaces observed in complexes involved in signal transduction and homodimers correlates with the presence of conformation changes, often implicated in biological function. Results of the CAPRI (critical assessment of predicted interactions) blind prediction experiment show that docking algorithms efficiently and accurately predict the mode of assembly of proteins that do not change conformation when they associate. They perform less well in the presence of large conformation changes and the experiment stimulates the development of novel procedures that can handle such changes.

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“…It is also suggested that the most binding energy is related only to several amino acids from the interface, so called "hot spots" [54][55][56][57]. Thus, the same forces are involved in protein-protein interaction, protein folding and ligand-receptor interaction.…”

Section: Thermodynamics and Kinetics Of Protein-protein Interactionsmentioning

confidence: 99%

Protein‐protein interactions as a target for drugs in proteomics

et al. 2003

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Protein-protein interactions play a central role in numerous processes in the cell and are one of the main fields of functional proteomics. This review highlights the methods of bioinformatics and functional proteomics of protein-protein interaction investigation. The structures and properties of contact surfaces, forces involved in protein-protein interactions, kinetic and thermodynamic parameters of these reactions were considered. The properties of protein contact surfaces depend on their functions. The contact surfaces of permanent complexes resemble domain contacts or the protein core and it is reasonable to consider such complex formation as a continuation of protein folding. Characteristics of contact surfaces of temporary protein complexes share some similarities with active sites of enzymes. The contact surfaces of the temporary protein complexes have unique structure and properties and they are more conservative in comparison with active site of enzymes. So they represent prospective targets for a new generation of drugs. During the last decade, numerous investigations were undertaken to find or design small molecules that block protein dimerization or protein(peptide)-receptor interaction, or, on the contrary, to induce protein dimerization.

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Anatomy of hot spots in protein interfaces

Cited by 1,830 publications

References 64 publications

Computational characterization of B-cell epitopes

Computational characterization of B-cell epitopes

Macromolecular recognition in the Protein Data Bank

Protein‐protein interactions as a target for drugs in proteomics

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