Monte Carlo Simulation Studies of Peptides (e.g. HIV-1 gp41 and its Structural Analogs) 
in Bilayer Membranes

Michael Maddox (Postdoctoral Associate)
David Mobley (Ph.D. Physics U C Davis, 2004)

Recent Project Progress:
Experiments have shown that the ability of the HIV-1 virus to infect cells can be greatly diminished by deactivation of the N-terminal (fusion) peptide of its glycoprotein gp41.  Deactivation can be achieved by the deletion of several amino acid residues, or replacement of a hydrophobic residue with a polar residue, to form mutant variants of the wild-type peptide. We report Monte Carlo simulation studies of a simplified peptide/membrane model, representing the interaction of an HIV-1 fusion peptide (FP) and four closely related mutagens with a lipid bilayer.  In agreement with experimental results, we show that FP inserts deeply into the bilayer at approximately 40º to the bilayer normal.  We also show a previously unreported behavior of membrane peptides, namely their equilibrium partitioning between several distinct conformations within the bilayer. We quantify this partitioning behavior and characterize each conformation in terms of its geometry, energy, and entropy.  The diminished ability of FP mutagens to hemolyse and aggregate red blood cells (RBC) due to their partitioning into unfavorable conformations, is also discussed. Our analysis supports a negative curvature mechanism for RBC hemolysis by FP.  We also suggest that the small repulsive forces between surface adsorbed peptides in opposing membrane surfaces may block aggregation.


Recent Project Publications:
"A Monte Carlo Study of Peptide Insertion into Lipid Bilayers: Equilibrium Conformations and Insertion Mechanisms", Biophysical Journal, Maddox, M. W., Longo, M. L. 2002, 82: 244-263.
“Conformational Partitioning of the Fusion Peptide of HIV-1 gp41 and its Structural Analogs in Bilayer Membranes” Biophysical Journal, Maddox, M. W., Longo, M. L., 2002, 83: 3088-3096.
“Modeling Amyloid b Peptide Insertion into Lipid Bilayers”  Mobley, D. L., Cox, D. L., Singh, R. R. P., Maddox, M. W., Longo, M. L. , 2004, Biophysical Journal, 86: 3585-3597.

Methods and Results:

Representative snapshots of the five membrane conformational states observed for FP and its
variants; (sa) surface adsorbed;  (527pi) partially inserted - tethered at residue 527;  (529pi)
partially inserted - tethered at residue 529; (fi) fully inserted;  (tb) trans-bilayer. The N-terminal
residue is indicated by a white circle, and the C-terminal residue by a black circle. The conformational
states, 527pi, 529pi, are specific to FP527L/R and FP529F/Y respectively, so the replacement residue
 is indicated in each case.  Although several peptides partition into the tb state, only FP520V/E favors
 this conformation over all others.  The replacement residue for FP520V/E is therefore indicated in the tb figure.



Gibbs energy level diagrams (not to scale) illustrating the conformational partitioning of wild-type FP and its
variants.  The energy level corresponding to a particular conformational state is labeled parenthetically as
follows; (ap) aqueous phase, (sa) surface adsorbed, (pi) partially inserted, (fi) fully inserted, (tb) trans-bilayer. 
Although each conformational state comprises a large number of closely related conformations, and therefore
a distribution of quantum energy levels, only the energy levels of the representative conformations for each state
are shown.  The groups of small vertical lines represent the relative population of each energy level (i.e. the partitioning)
at equilibrium. Although the absolute Gibbs energy of the fi state is different for each peptide, all fi states are shown
at the same energy level in the figure, to illustrate the relative energy changes of the other conformational states.