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Book of Abstracts: Albany 2005

category image Volume 22
No. 6
June 2005

Retroviral Matrix Domains Share Electrostatic Homology: Models for Membrane Binding Function Throughout the Viral Life Cycle

The matrix domain (MA) of Gag polyproteins performs multiple functions throughout the retroviral life cycle. Known MA structures have an electropositive surface patch that has been implicated in membrane association. Here we use computational methods to demonstrate that electrostatic control of membrane binding is a central characteristic of all retroviruses. We are able explain a wide range of experimental observations on MA and provide a level of quantitative and molecular detail that has been inaccessible to experiment. We further predict that MA exists in oligomerization states previously not considered and propose mechanistic models for the effects of phosphoinositides and phosphorylation. Our calculations provide a new conceptual model for how non-myristoylated and myristoylated MAs behave similarly in assembly and disassembly. As such they provide a unified quantitative picture of the structural and energetic origins of the entire range of MA function and thus enhance, extend and integrate previous observations on individual stages of the process.

Summary sentence

Computational biophysics provides the first comprehensive model that shows how electrostatic interactions play both a primary role in mediating the membrane association of both myristoylated and non-myristoylated Gag polyproteins and important regulatory roles during viral assembly, maturation and infection.

Acknowledgements

This work was supported by NIH grant AI54167 and NSF grant MCB030028 for advanced computational resources at the Pittsburgh Supercomputing Center (DM). Support from NSF grant MCB-0416708 is also acknowledged (BH). We are grateful to Stephen J. Matthews for the coordinates of BLV MA and to Stephen Goff, Volker Vogt and Amanda Dalton for stimulating discussions.

Paul S. Murray1
Zhaohui Li1
Jiyao Wang1
Chris L. Tang2
Barry Honig2
Diana Murray1,*

1Department of Microbiology and Immunology
The Institute for Computational Biomedicine
Weill Medical College of Cornell
New York, NY 10021
2Howard Hughes Medical Institute
Department of Biochemistry and Molecular Biophysics
Columbia University
New York, NY 10032

*Corresponding author:
Phone: 212-746-1184
Fax: 212-746-8587
Email: dim2007@med.cornell.edu