Andres Tellez, Ph.D.
Postdoctoral Fellow

Education:

Ph.D. Bioinformatics, Stanford University, 2007.
M.Eng. Electrical Engineering and Computer Science, Massachusetts Institute of Technology, 2000.
S.B. Computer Science, Massachusetts Institute of Technology, 2000.

 
Address:
D321 Fairchild
299 Campus Drive
Stanford CA 94305-5124
 
Telephone:
+1.650.498.7085
 
E-mail:
   
Research Summary

The poliovirus replication complex involves the viral RNA-dependent RNA polymerase in oligomeric complexes on the surface of membranes. The poliovirus polymerase assembles into two-dimensional lattices that display cooperative catalytic activity (Science 296:5576, 2002) and viruses that contain polymerase mutations have been shown to be dominant negative (Nat. Genet 37:701, 2005). Lattice formation requires two sets of polymerase-polymerase contacts; characterizing this protein-protein interaction is an important step in the design of novel antiviral therapies. One polymerase-polymerase interaction site, Interface I, has been identified and validated by previous work (Structure 5:1109 1997; EMBO 20:1153 2001, JBC 277:31551 2002). Interface I is an asymmetric interaction which forms extendable head to tail fibers of polymerase.To form planar lattices, a second oligomeric interface must exist to stack up interface I fibers. To generate plausible hypotheses about this second oligomeric interface, computational modeling was employed.

To model the potentially alternative polymerase conformations that might be sampled, low frequency harmonic oscillations were calculated using normal mode analysis. Ten such alternative conformations were modeled into polymerase-polymerase fibers. The surface convolution was calculated for one hundred pairs of fibers, creating thousands of complexes. The complexes were then filtered for those that formed interactions that could be propagated into large lattices. Selection of the symmetric and parsimonious interfaces within the family of parallel and anti-parallel sheets resulted in four candidate interfaces involving distinct patches of residues on the polymerase. Multiple sequence alignment of every known picornavirus polymerase exhibits high conservation and co-variation within the regions that make up the postulated second interface. The wavelength-dependence of turbidity during protein oligomerization will be used to evaluate the kinetics and extent of polymerase oligomerization for wild type polymerase and polymerase that contains mutations designed to disrupt the posited second interface.

Copyright 2006 - 2007. The Laboratory of Karla Kirkegaard, Ph.D. All rights reserved.