A reinterpretation of neutron scattering experiments on a lipidated Ras peptide using replica exchange molecular dynamics

Abstract

The Ras family of proteins plays crucial roles in a variety of cell signaling networks where they have the function of a molecular switch. Their particular medical relevance arises from mutations in these proteins that are implicated in ~30% of human cancers. The various Ras proteins exhibit a high degree of homology in their soluble domains but extremely high variability in the membrane anchoring regions that are crucial for protein function and are the focus of this study. We have employed replica exchange molecular dynamics computer simulations to study a doubly lipidated heptapeptide, corresponding to the C-terminus of the human N-Ras protein, incorporated into a dimyristoylphosphatidylcholine lipid bilayer. This same system has previously been investigated experimentally utilizing a number of techniques, including neutron scattering. Here we present results of well converged simulations that describe the subtle changes in scattering density in terms of the location of the peptide and its lipid modifications and in terms of changes in phospholipid density arising from the incorporation of the peptide into the membrane bilayer. The detailed picture that emerges from the combination of experimental and computational data exemplifies the power of combining isotopic substitution neutron scattering with atomistic molecular dynamics simulation. This article is part of a Special Issue entitled: Membrane protein structure and function.

Structural Behavior of the Peptaibol Harzianin HK VI in a DMPC Bilayer: Insights from MD Simulations

“…MAPs have been also a subject of work applying advanced simulation techniques. The temperature replica exchange protocol (replica-exchange MD) (40) was exploited in structural studies (41)(42)(43)(44). The dissipative particle dynamics (45), which is a variant of CG MD, was applied in a study of pore formation and other bilayer deformations caused by several different MAPs (46).…”

A Microscopic View of Phospholipid Insertion into Biological Membranes

“…4–7 These physiocochemical properties are determined by phospholipid composition, which is in turn controlled by monomeric phospholipid exchange or vesicular transport. 8 This suggests that the membrane itself is an active participant in orchestrating the symphony of motion across cellular membranes, whether it be by facilitating drug binding, 9–12 mediating the activity of proteins, 13–16 the association and insertion of membrane actors, 17,18 and in membrane fusion. 19,20 …”

The interactions of peripheral membrane proteins with biological membranes

“…Neutron reflectometry is used to study the interactions at solidsupported membrane interfaces (Harroun et al, 2005) while SANS can be used to study protein interactions with membrane vesicles in solution (Kucerka et al, 2004). Recent advances in the development of accurate theoretical representations of biological membranes using molecular dynamics (MD) simulations enables interpretation of neutron scattering data and with far higher accuracy (Heberle et al, 2012;Vogel et al, 2012). MD simulations inherently account for disorder as a result of thermal fluctuations and are particularly useful for visualizing the interactions between proteins and individual lipid molecules (Demchenko and Yesylevskyy, 2009).…”