Abstract
Two new computational approaches are described to aid in the design of new peptide-based drugs by evaluating ensembles of protein structures from their dynamics and through the assessing of structures using empirical contact potential. These approaches build on the concept that conformational variability can aid in the binding process and, for disordered proteins, can even facilitate the binding of more diverse ligands. This latter consideration indicates that such a design process should be less restrictive so that multiple inhibitors might be effective. The example chosen here focuses on proteins/peptides that bind to hemagglutinin (HA) to block the large-scale conformational change for activation. Variability in the conformations is considered from sets of experimental structures, or as an alternative, from their simple computed dynamics; the set of designe peptides/small proteins from the David Baker lab designed to bind to hemagglutinin, is the large set considered and is assessed with the new empirical contact potentials.
Highlights
Influenza infection is a widespread cause of major medical concern because of rapid viral evolution, which causes both occasional pandemics and, more frequently, health problems almost every year
Hemagglutinin (HA) is a major surface glycoprotein of this virus that is involved in four of the most important aspects of influenza infection: (a) it is the target of antibodies that neutralize infectivity, (b) it undergoes antigenic drift to escape neutralization, (c) it binds to cell-surface receptors to initiate infection, and (d) it mediates the fusion of viral and host membranes essential for viral entry
The large-scale conformational changes in HA are critical for the steps in which the virus inserts itself into the host cells by fusing to the host membrane, and the residues involved in this process are highly conserved across different types and subtypes during antigenic drift
Summary
Influenza infection is a widespread cause of major medical concern because of rapid viral evolution, which causes both occasional pandemics and, more frequently, health problems almost every year. Vaccination offers limited protection, especially when facing the highly virulent nature and rapid evolution of influenza (Chen et al, 1999). Hemagglutinin (HA) is a major surface glycoprotein of this virus that is involved in four of the most important aspects of influenza infection: (a) it is the target of antibodies that neutralize infectivity, (b) it undergoes antigenic drift to escape neutralization, (c) it binds to cell-surface receptors to initiate infection, and (d) it mediates the fusion of viral and host membranes essential for viral entry.
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