Proteins in the Order–Disorder Twilight: Unstable Interfaces Promote Protein Aggregation

  • Ariel Fernández Stigliano


Soluble folded proteins maintain their structural integrity by properly shielding their backbone amides and carbonyls from hydration. Thus, a poorly wrapped backbone hydrogen bond or dehydron constitutes an identifiable structural deficiency. In this chapter we describe the physical properties of proteins that possess significant clusters of dehydrons in their soluble structure. We show that these clusters represent unique structural singularities belonging to an order–disorder twilight zone and generate a sharp local quenching of the dielectric permittivity of the surrounding medium. The functional roles of these singularities are explored across natural proteins and related to their physical properties. Special emphasis is placed on the molecular etiology of aberrant amyloidogenic aggregation arising in soluble proteins with large deviations from the golden rule of molecular architecture established in Chap. 1. Our analysis of unstable aqueous interfaces requires a description of biological water that cannot be properly captured by conventional continuous models, where solvent degrees of freedom are typically averaged out. The order–disorder twilight arising from high dehydron concentration is a topic of intense scrutiny, as we show how to predict such regions based solely on sequence information. The predictive tools are applied in the problems section to engineer a pharmaceutical disruptive of a protein–protein interaction as a potential therapeutic agent to treat heart failure. We should emphasize that the disruption of protein–protein interfaces is viewed as a holy grail in drug discovery.


Bulk Water Packing Defect Solvate Water Molecule Yeast Prion Sequence Window 
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Copyright information

© Springer International Publishing Switzerland 2015

Authors and Affiliations

  1. 1.National Research Council–CONICETBuenos AiresArgentina
  2. 2.Former Karl F. Hasselmann Endowed Chair Professor of BioengineeringRice UniversityHoustonUSA

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