Membrane localization and flexibility of a lipidated ras peptide studied by molecular dynamics simulations

TitleMembrane localization and flexibility of a lipidated ras peptide studied by molecular dynamics simulations
Publication TypeJournal Article
Year of Publication2004
AuthorsGorfe A.A, Pellarin R., Caflisch A.
JournalJournal of the American Chemical Society
Volume126
Issue46
Pagination15277-15286
Date Published2004 Nov 24
Type of ArticleResearch Article
ISSN0002-7863
KeywordsComputer Simulation, Dimyristoylphosphatidylcholine, Humans, Hydrophobic and Hydrophilic Interactions, Lipid Bilayers, Lipoproteins, Models, Molecular, Nuclear Magnetic Resonance, Biomolecular, Peptide Fragments, Protein Structure, Secondary, ras Proteins, Thermodynamics, Water
Abstract

Lipid-modified membrane-binding proteins are essential in signal transduction events of the cell, a typical example being the GTPase Ras. Recently, membrane binding of a doubly lipid-modified heptapeptide from the C-terminus of the human NRAS protein was studied by spectroscopic techniques. It was found that membrane binding is mainly due to lipid chain insertion, but it is also favored by interactions between apolar side chains and the hydrophobic region of the membrane. Here, 10 explicit solvent molecular dynamics simulations for a total time of about 150 ns are used to investigate the atomic details of the peptide-membrane association. The 16:0 peptide lipid chains are more mobile than the 14:0 phospholipid chains, which is in agreement with 2H NMR experiments. Peptide-lipid and peptide-solvent interactions, backbone and side-chain distributions, as well as the effects of lipidated peptide insertion onto the structure, and dynamics of a 1,2-dimyristoylglycero-3-phosphocholine bilayer are described. The simulation results validate the structural model proposed by the analysis of spectroscopic data and highlight the main aspects of the insertion mechanism. The peptide in the membrane is rather rigid over the simulation time scale of about 10 ns, but different partially extended conformations devoid of backbone hydrogen bonds are observed in different trajectories.

DOI10.1021/ja046607n
pubindex

0062

Alternate JournalJ. Am. Chem. Soc.
PubMed ID15548025
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