Abstract
Ebola, considered till recently as a rare and endemic disease, has dramatically transformed into a potentially global humanitarian crisis. The genome of Ebola, a member of the Filoviridae family, encodes seven proteins. Based on the recently implemented software (PAGAL) for analyzing the hydrophobicity and amphipathicity properties of alpha helices (AH) in proteins, we characterize the helices in the Ebola proteome. We demonstrate that AHs with characteristically unique features are involved in critical interactions with the host proteins. For example, the Ebola virus membrane fusion subunit, GP2, from the envelope glycoprotein ectodomain has an AH with a large hydrophobic moment. The ability of this AH to bind to other host proteins is disrupted by a neutralizing antibody derived from a human survivor of the 1995 Kikwit outbreak, emphasizing the critical nature of this secondary structure in the virulence of the Ebola virus. Our method ensures a comprehensive list of such `hotspots'. These helices probably are or can be the target of molecules designed to inhibit AH mediated protein-protein interactions. Further, by comparing the AHs in proteins of the related Marburg viruses, we are able to elicit subtle changes in the proteins that might render them ineffective to previously successful drugs. Such differences are difficult to identify by a simple sequence or structural alignment. Thus, analyzing AHs in the small Ebola proteome can aid rational design aimed at countering the `largest Ebola epidemic, affecting multiple countries in West Africa' (http://www.cdc.gov/vhf/ebola/outbreaks/2014-west-africa/index.html).
Highlights
The Ebola virus was first discovered in 19761, and has been since known as a rare, but deadly disease2
The Ebola virus potently suppresses the human immune response2,6,35 by binding with key human proteins involved in the immune pathway18
These protein-protein interactions are often mediated through well structured secondary regions within the protein structures, and the design of molecules that inhibit these ‘hotspots’20,36 has been a well known strategy to develop drugs to counter bacterial and viral infections10–12
Summary
The Ebola virus was first discovered in 19761, and has been since known as a rare, but deadly disease. Along with the Marburg virus, belongs to the Filoviridae family, and causes haemorrhagic fever by quickly suppressing innate antiviral immune responses to facilitate uncontrolled viral replication. The genome of the Ebola virus encodes seven proteins, their extreme ‘plasticity allows multiple functions’. Protein structures are formed by well ordered local segments, of which the most prevalent are alpha helices (AH) and β sheets. AHs are right-handed spiral conformations which have a hydrogen bond between the carbonyl oxygen (C=O) of each residue and the alpha-amino nitrogen (N-H) of the fourth residue away from the N-terminal. We have provided open access to software that has reproduced previously described computational methods to compute the hydrophobic moment of AHs (PAGAL14)
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