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  • Oral presentation
  • Open Access

Competition between protein aggregation and protein complex formation

  • 1Email author,
  • 2,
  • 1 and
  • 1
BMC Bioinformatics20089 (Suppl 10) :O2

  • Published:


  • Protein Aggregation
  • Disulphide
  • Salt Bridge
  • Molecular Recognition
  • Negative Peak


Interactions between proteins are vital for essentially every process in a living cell. Physico-chemical complementarity, which can be considered as the driving force for molecular recognition, has been found to not consistently explain protein-ligand interactions. As aberrant interactions should be avoided in order to maintain cell viability, promoting complex formation and preventing protein aggregation are two opposite requirements on the physico-chemical properties of protein surfaces.


As a first step, aggregation propensity profiles were calculated using the Zyggregator algorithm [13], which takes hydrophobicity, charge, structural propensities and alternating hydrophobic-polar patterns into account. Positive peaks in these profiles indicate regions that promote aggregation while negative peaks identify regions preventing aggregation. These calculations are based on individual aggregation propensities for each amino acid based on their physico-chemical properties and experimentally determined [13]. The aggregation propensity profiles were then mapped onto the structures of protein complexes [4] and aggregation propensity patches of interfaces and surfaces were compared.


We found that interface regions of the analysed protein complexes are on average more aggregation prone than other surface regions (see Figure 1). The aggregation propensity is more effective than hydrophobicity for identifying such interfaces. Our results indicate that the determinants of protein complex formation are similar to those of protein aggregation. We further show that the competition between these two processes is mediated by the presence of disulphide bonds and salt bridges, which have evolved as negative design principles to prevent interfaces from triggering uncontrolled aggregation (see Figure 1).
Figure 1
Figure 1

Protein aggregation propensity surfaces, red indicates aggregation prone regions and blue aggregation resistant regions. A The aggregation prone interface of the 'mainly-β' – homodimer complex (PDB structure: 1XSO) is stabilized by a disulphide-bond (in 'sticks' representation). B Aggregation prone interface of an 'mainly-α' homo-dimeric protein complex (1BBH). C Aggregation prone interface of a cyclic trimeric protein complex (1KRR). D Aggregation propensity surface of the aggregation resistant and monomeric human myoglobin protein (2MM1).


The specificity in molecular recognition is achieved through a combination of positive and negative design principles, which, respectively, promote the assembly of functional complexes and prevent the formation of potentially dangerous aggregates.



The molecules in the figure were rendered using PyMOL (W.L. DeLano,

Authors’ Affiliations

Department of Chemistry, University of Cambridge, Cambridge, CB2 1EW, UK
MRC Laboratory of Molecular Biology, Cambridge, CB2 0QH, UK


  1. DuBay KF, Pawar AP, Chiti F, Zurdo J, Dobson CM, Vendruscolo M: Prediction of the absolute aggregation rates of amyloidogenic polypeptide chains. J Mol Biol 2004, 341(5):1317–26. 10.1016/j.jmb.2004.06.043View ArticlePubMedGoogle Scholar
  2. Pawar AP, Dubay KF, Zurdo J, Chiti F, Vendruscolo M, Dobson CM: Prediction of "aggregation-prone" and "aggregation-susceptible" regions in proteins associated with neurodegenerative diseases. J Mol Biol 2005, 350(2):379–92. 10.1016/j.jmb.2005.04.016View ArticlePubMedGoogle Scholar
  3. Tartaglia GG, Pawar AP, Campioni S, Dobson CM, Chiti F, Vendruscolo M: Prediction of aggregation-prone regions in structured proteins. J Mol Biol 2008, 380(2):425–36. 10.1016/j.jmb.2008.05.013View ArticlePubMedGoogle Scholar
  4. Levy ED, Pereira-Leal JB, Chothia C, Teichmann SA: 3D complex: a structural classification of protein complexes. PLoS Comput Biol 2006, 2(11):e155. 10.1371/journal.pcbi.0020155PubMed CentralView ArticlePubMedGoogle Scholar


© Pechmann et al; licensee BioMed Central Ltd 2008

This article is published under license to BioMed Central Ltd.