Simulation-based methods for interpreting X-ray data from lipid bilayers

The fully hydrated liquid crystalline phase of the dimyristoylphosphatidycholine lipid bilayer at 30 degrees C was simulated using molecular dynamics with the CHARMM potential for five surface areas per lipid ( A) in the range 55-65 angstrom(2) that brackets the previously determined experimental area 60.6 angstrom(2). The results of these simulations are used to develop a new hybrid zero-baseline structural model, denoted H2, for the electron density profile, p(z), for the purpose of interpreting x-ray diffraction data. H2 and also the older hybrid baseline model were tested by fitting to partial information from the simulation and various constraints, both of which correspond to those available experimentally. The A, p(z), and F(q) obtained from the models agree with those calculated directly from simulation at each of the five areas, thereby validating this use of the models. The new H2 was then applied to experimental dimyristoylphosphatidycholine data; it yields A 60.6 +/- 0.5 angstrom(2), in agreement with the earlier estimate obtained using the hybrid baseline model. The electron density profiles also compare well, despite considerable differences in the functional forms of the two models. Overall, the simulated p( z) at A 60.7 angstrom(2) agrees well with experiment, demonstrating the accuracy of the CHARMM lipid force field; small discrepancies indicate targets for improvements. Lastly, a simulation-based model-free approach for obtaining A is proposed. It is based on interpolating the area that minimizes the difference between the experimental F( q) and simulated F( q) evaluated for a range of surface areas. This approach is independent of structural models and could be used to determine structural properties of bilayers with different lipids, cholesterol, and peptides.