Mikko Huhtala

Åbo Akademi University
Supervisor: Mark S. Johnson
Funding: other
Date: 31/5/2001

Molecular modeling of virus-receptor interactions

Picornaviridae is a family of icosahedral non-enveloped viruses that includes several important human pathogens such as hepatitis viruses and poliovirus. The research project focuses on the interactions of viruses with cell surface receptors in order to explain the detailed mechanism of virus binding and uncoating. Three-dimensional protein and virus structures have traditionally been determined by X-ray crystallography, which requires well-ordered crystals of the sample. Cryo-electron microscopy (cryo-EM) of single particles, combined with image analysis and three-dimensional reconstruction, is emerging as a key technique in structural biology. This structure determination method can tackle large molecular complexes and does not require a crystalline sample. We collaborate with professor R. Holland Cheng, a pioneer of the cryo-electron microscopy methods, whose research group at the Karolinska Institute in Sweden specializes in the structure determination of viruses and virus-receptor complexes by cryo-EM.

In contrast to crystallography, cryo-EM of single particles cannot currently reach atomic resolution. Therefore, the detailed modeling of large complex structures relies on fitting atomic-resolution models of the component structures to the low-resolution electron density maps generated by cryo-EM. Our collaboration with professor Cheng's group includes molecular modeling of structures for which cryo-EM data can be provided. We have modeled interactions of the alpha2 integrin I-domain with human echovirus 1, a member of Picornaviridae, on the basis of cryo-EM measurements. Echovirus 1 is a common cause of enteric infections and understanding the mechanism of echovirus entry into host cells can help in the design of drug molecules to inhibit this process and possibly lead to a novel antiviral therapy. Moreover, we are developing a comparative three-dimensional model of hepatitis virus A, which can be used to interpret antibody epitope mapping and mutagenesis results and to provide testable hypotheses for cryo-EM experiments.

In the future, we aim to develop methods and computer software to automate fitting of atomic-resolution models of component proteins to low-resolution cryo-EM electron density maps in addition to work on specifc modeling problems of biological relevance.