A Molecular Dynamics Study of Ras Clustering in Membrane Domains

Abstract

Ras proteins are small GTP-hydrohydrolyzing enzymes that function as conformational switches controlling cell proliferation, differentiation, and development. Ras nanolcustering on the plasma membrane and segregation of the clusters into specific membrane substructure driven by competing effects from the lipidated C-terminus and the globular catalytic domain, has attracted much interest in recent years. In this work, we study the clustering behavior of the full length H-ras protein in a model membrane using coarse-grained Molecular Dynamics (MD) simulations. Our model membrane is a phase-separted bilayer comprised of 3840 DPPC, 2304 DLiPC and 1536 cholesterol molecules. Initial results from the simulations suggest that the same fundamental forces that drive clustering of the minimal H-ras membrane anchor also underlie the clustering behavior of the whole protein. However, steric effects in the full-length protein modulate the size and distribution of its clusters, as well as the elastic properties of the bilayer. The results provide previously unavailable molecular insight into the nanoscale organization of lipidated proteins on the plasma membrane.