TITLE:

H-RAS PROTEIN IN A DMPC BILAYER: COMPUTATIONAL ANALYSIS OF INSERTION FREE ENERGY AND MEMBRANE STRUCTURE PERTURBATION (No. 144)

DATE:

Friday, May 4th, 2007

TIME:

3:30 PM

LOCATION:

GMCS 214

SPEAKER:

Alemayehu Gorfe, Department of Chemistry and Biochemistry, University of California at San Diego

ABSTRACT:

Ras proteins are GTPases that mediate signal transduction pathways that control cell growth and proliferation. They are active when anchored to the inner surface of plasma membrane by inserting their lipid modified side chains into the hydrophobic core of the membrane. The structure of the protein-membrane complex was not known. Using modeling and molecular dynamics simulations, we have recently characterized the structure of the full-length H-ras protein in a DMPC bilayer [Gorfe AA, Hanzel-Bayer M, Abankwa D, Hancock JF and McCammon JA, J. Med. Chem., 2007]. We found that ras binding to membrane involves, in addition the anchor, a direct interaction with the membrane phosphates of positively charged residues from either the linker or the catalytic domain. These two modes of interaction differently affect both the orientation of the catalytic domain relative to the membrane plane and the structure and dynamics of the bilayer. Moreover, we observed differential localization of the backbone of the anchor when it is inserted alone versus together with the linker or the linker and the GDP/GTP bound catalytic domain. We have now computed the potential-of-mean-force for the insertion of the lipid-anchor into a DMPC bilayer. This data enabled us derive a possible mechanism for the membrane microdomain preferences of H-ras and its fragments. I will discuss these recent computational results and highlight their biological significance using experimental data generated by our collaborators.

HOST:

Sam Kassegne

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