Computational modeling of the hypervariable region (HVR) of K-Ras4B protein

Friday, November 08, 2013 — Poster Session IV
2:00 p.m. – 4:00 p.m.	FAES Academic Center (Upper-Level Terrace)	NCI	COMPBIO-7

Authors

H. Jang
N. Tarasova
V. Gaponenko
R. Nussinov

Abstract

Ras is a membrane-associated guanine nucleotide-binding protein that is normally activated in response to the binding of extracellular signals through membrane receptors to intracellular signaling cascades. The protein contains approximately 188 amino acids with highly conserved residues 1-166 and with considerably variable C-terminal hypervariable region (HVR). Recent NMR experiments discovered that the HVR of GDP-bound K-Ras4B extensively interacts with the catalytic domain, while the HVR of GTP-bound K-Ras4B weakly interacts with the catalytic domain. Here we modeled the HVR of K-Ras4B using explicit molecular dynamics (MD) simulations. X-ray crystal structures only provide the highly conserved residues 1-166, while no structural information for the C-terminal HVR is currently available. Membrane binding of K-Ras4B through anchoring of the positively charged HVR is critical to its function as an oncogene and initiates signaling events. In our simulations, we observed that derivatives of the HVR interact with the catalytic domain of K-Ras4B in solution. The farnesyl group of cysteine residue in the post-translationally modified HVR spontaneously inserted into the zwitterionic (DOPC) and anionic (DOPC:DOPS=4:1) bilayers. We further modeled a full structure of K-Ras4B with the farnesylated HVR interacting with the lipid bilayer, suggesting the mechanisms of functional and conformational Ras On and Off states.