BIOPHYSICAL THEORY AND MODELING |
DIFFRACTION-BASED DENSITY RESTRAINTS FOR MEMBRANE AND
MEMBRANE-PEPTIDE MOLECULAR DYNAMICS SIMULATIONS
Ryan W Benz 1, Hirsh Nanda 2, Francisco Castro-Román 2, Stephen H. White 3* and Douglas J. Tobias 2
1 University of California, Irvine
2 University of California at Irvine
3 Univ. of California at Irvine
* To whom correspondence should be addressed. E-mail: blanco{at}helium.biomol.uci.edu.
Submitted on March 6, 2006
Revised on April 12, 2006
Accepted on 9 August 2006
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Abstract |
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Benz et al. (Biophys. J. 88:805-817, 2005) have shown that current molecular dynamics (MD) atomic force fields are not yet able to produce lipid bilayer structures that agree with experimentally-determined structures within experimental errors. Because of the many advantages offered by experimentally validated simulations, we have developed a novel restraint method for membrane MD simulations that uses results from experimental diffraction data. The restraints, introduced into the MD force field, act upon specified groups of atoms to restrain their mean position and width to values determined experimentally. The method was first tested using a simple liquid argon system, and then applied to a neat dioleoylphosphatidylcholine (DOPC) bilayer at 66% relative humidity and to the same bilayer containing the peptide melittin (MLT). Application of experiment-based restraints to the transbilayer double-bond and water distributions of neat DOPC bilayers led to distributions that agreed with the experimental values. Based upon the experimental structure, the restraints improved the simulated structure in some regions while introducing larger differences in others, as might be expected from imperfect force fields. For the DOPC-MLT system, the experimental transbilayer distribution of melittin was used as a restraint. The addition of the peptide caused perturbations of the simulated bilayer structure, but which were larger than observed experimentally. The melittin distribution of the simulation could be fit accurately to a Gaussian with parameters close to the observed ones, indicating that the restraints can be used to produce an ensemble of membrane-bound peptide conformations that are consistent with experiments. Such ensembles open the way for understanding peptide-bilayer interactions at the atomic level.
Key Words:
DOPC, melittiin, neutron diffraction, scattering-density profiles, x-ray diffraction
