Skip to: main navigation | content

SLAC National Accelerator Laboratory

SSRL Aids Computational Design of Anti-flu Proteins
SSRL Science Summary - August 2012

Figure 1.
Computationally designed protein bound to the surface of Spanish flu (H1N1) hemagglutinin.

Understanding how proteins interact with some specific molecules and not with the myriad other molecules with which they coexist in every cellular compartment is a major goal of molecular biology. Linus Pauling suggested the broad outlines of an answer in the 1940's: the aggregate effect of numerous weak and nonspecific van der Waals, hydrogen-bonding, and electrostatic interactions are what underlie high specificity and affinity.


In recent papers, a group of researchers led by David Baker (University of Washington) provided the first high-affinity and high-specificity interactions designed entirely from scratch. X-ray diffraction data collected on Beam Line 9-2 at SSRL played a key role in the validation of the two best designs. In the process of developing the computational methods, the team made breakthroughs in understanding the design principles of natural functional sites.


The team targeted a surface on the influenza hemagglutinin protein that enables flu viruses to attach to and invade cells lining the human respiratory tract. They used massively parallel computing to sift through numerous configurations of more than 800 natural proteins, searching for the few configurations predicted to form numerous weak interactions with the target hemagglutinin surface. Binding experiments then isolated two designed proteins which bound specifically to the target site. Following further optimization the two proteins were shown to bind to Spanish and avian flu hemagglutinin with very high affinity and blocked the replication of H1N1 flu viruses in human cell cultures. Crystal structures of these proteins bound to Spanish flu hemagglutinin were virtually indistinguishable from the designed models, providing crucial atomic-level validation for the computational methods. These proteins are now being developed as potential therapeutics against a wide range of pathogenic flu viruses. If successful, this would mark the first example of de novo-designed proteins with therapeutic applications.


Primary Citation


  1. "Computational design of proteins targeting the conserved stem region of influenza hemagglutinin." Fleishman SJ, Whitehead TA, Ekiert DC, Dreyfus C, Corn JE, Strauch EM, Wilson IA, Baker D. Science. 2011 May 13;332(6031):816-21.


Related Links

Full Science Highlight

PDF Version


Contacts

Sarel Fleishman, Weizmann Institute of Science
David Baker, University of Washington
Ian Wilson, The Scripps Research Institute



2575 Sand Hill Road, MS: 99, Menlo Park, California, 94025, USA Tel: 650-926-4000 | Fax: 650-926-4100