We employ 50 ns molecular dynamics simulations to study the distribution, orientation, and dynamics of 1,6-diphenyl-1,3,5-hexatriene (DPH) fluorescent probes in a dipalmitoylphosphatidylcholine (DPPC) bilayer. We find no evidence for clustering of DPH molecules, and our results show that DPH does not prefer to be embedded in the membrane center where free volume is largest. Rather, DPH prefers to be accommodated in the hydrophobic acyl chain region of DPPC, oriented such that the long axis of DPH along its rodlike shape is approximately aligned in the direction of the bilayer normal, thus reflecting the ordering of lipid acyl chains. These conclusions are supported by further studies of radial distribution functions indicating DPH to be located beside the lipid acyl chains. Studies of DPH dynamics in DPPC bilayers reveal a number of rare events, including flip-flops of DPH molecules from one leaflet to another, their rotational diffusion whose time scale can be compared with that found through experiments, and the lateral diffusion of DPH in the plane of the bilayer. For lateral diffusion of DPH, we consider its diffusion mechanism and find that to take place through jumps from one void to another. In all, our results are in favor of using DPH for probing lipid membranes.

We have conducted extensive molecular dynamics (MD) simulations together with differential scanning calorimetry (DSC) and nuclear magnetic resonance (NMR) experiments to quantify the influence of free 1,6-diphenyl-1,3,5-hexatriene (DPH) fluorescent probes on the structure and dynamics of a dipalmitoylphosphatidylcholine bilayer. Atomistic MD simulations show that in the membrane-water interface the influence of DPH is minor, whereas in the acyl-chain region DPH gives rise to major perturbations. In the latter case, DPH is found to influence a wide range of membrane properties, such as the packing and ordering of hydrocarbon tails and the lateral diffusion of lipid molecules. The effects are prominent but of local nature, i.e., the changes observed in the properties of lipid molecules are significant in the vicinity of DPH, but reduce rapidly as the distance from the probe increases. Long-range perturbations due to DPH are hence not expected. Detailed DSC and (2)H NMR measurements support this view. DSC shows only subtle perturbation to the cooperative behavior of the membrane system in the presence of DPH, and (2)H NMR shows that DPH gives rise to a slight increase in the lipid chain order, in agreement with MD simulations. Potential effects of other probes such as pyrene are briefly discussed.

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