ct0501250_si_001.pdf (90.01 kB)
Helix Interactions in Membranes: Lessons from Unrestrained Monte Carlo Simulations
journal contribution
posted on 2005-11-08, 00:00 authored by Yana A. Vereshaga, Pavel E. Volynsky, Dmitry E. Nolde, Alexander S. Arseniev, Roman G. EfremovWe describe one of the first attempts at unrestrained modeling of self-association of
α-helices in implicit heterogeneous membrane-mimic media. The computational approach is
based on the Monte Carlo conformational search for peptides in dihedral angles space. The
membrane is approximated by an effective potential. The method is tested in calculations of
two hydrophobic segments of human glycophorin A (GpA), known to form membrane-spanning
dimers in real lipid bilayers. Our main findings may be summarized as follows. Modeling in
vacuo does not adequately describe the behavior of GpA helices, failing to reproduce
experimental structural data. The membrane environment stabilizes α-helical conformation of
GpA monomers, inducing their transmembrane insertion and facilitating interhelical contacts.
The voltage difference across the membrane promotes “head-to-head” orientation of the helices.
“Fine-tuning” of the monomers in a complex is shown to be regulated by van der Waals
interactions. Detailed exploration of conformational space of the system starting from arbitrary
locations of two noninteracting helices reveals only several groups of energetically favorable
structures. All of them represent tightly packed transmembrane helical dimers. In overall, they
agree reasonably well with mutagenesis data, some of them are close to NMR-derived structures.
A possibility of left-handed dimers is discussed. We assume that the observed moderate structural
heterogeneity (the existence of several groups of states with close energies) reflects a real
equilibrium dynamics of the monomersat least in membrane mimics used in experimental
studies of GpA. The elaborated computational approach is universal and may be employed in
studies of a wide class of membrane peptides and proteins.
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Keywords
noninteracting helicesGpA helicesinterhelical contactsvoltage differenceMonte Carlodihedral angles spacetransmembrane insertionapproachGpA monomerslipid bilayersmodelingmembrane peptidesvan der Waals interactionsmembrane mimicsmutagenesis dataUnrestrained Monte Carlo Simulationshelix Interactionsequilibrium dynamicstransmembrane helical dimersmembrane environment
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