MSOE Sandbox HA

From Proteopedia

Revision as of 21:51, 4 August 2011

Title: Hemagglutinin Bound to Antibody CR6261 and Bound de novo Protein HB36

Headline text

Abstract:

The threat of an influenza pandemic looms eminent in the future of public health around the globe, similar to the previous 1918 H1N1 Spanish flu, 1957 H2N2 Asian flu, and 1968 H3N2 Hong Kong flu epidemics. Synthesizing a broad-spectrum influenza vaccine remains elusive due to the highly mutable nature of the head region of the viral protein hemagglutinin (HA). However, it is known that the stem portion of this molecule is highly stable and that the human antibody CR6261 Fab can dock into a stem region binding site in the presence of low pH to activate the conformational change of HA. This allows the virus to fuse with the membrane of the host cell to initiate the viral infection. The development of a de novo protein molecule that mimics this docking action into the binding site was done computationally, and 88 designs were tested for effectiveness using the yeast strain EBY 100. Following affinity maturation, the 3R2X protein was shown to effectively bind at the conserved surface patch and inhibit the conformational change at low pH. This protocol of producing de novo designed proteins may alleviate the problem of producing sufficient quantities of CR6261 in the event of a pandemic.

Hemogglutin

Hemogglutin exists a functional trimer that begins influenza infection with a complex of other proteins. The each of the three HA proteins are constructed: HA1 and HA2 . The Hemaglutinin (HA) protein undergoes a major conformational shift to enable infection which involves several major helices of the HA2 chain. This region along with an adjacent region of the HA1 from the stem region of HA. Because this region is so important to the conformational change for functionality of this protein, this region is highly conserved across a variety of species of influenza (needs citation)and thus an ideal target to create a vaccine that will be effective against many strains of influenza. HA is divided into two regions . The Head region is highly mutable and thus poor target for drug design in vaccinations. The stem is highly conserved across multiple species of flu.