The latter is a theoretical model obtained from the Forster resonance energy transfer measurements. In this model, TM helices are less bended compared with the bellflower model, and the cytoplasmic helices are located in the plane of the membranes. Although several MD studies of partial or full length PLN in different environments have been reported, most of these studies are only focused on the monomeric PLN. So far only two papers are involved with the pentameric PLN. However, the one published by Kim et al. only used the bellflower models, while the other did not consider the phosphorylated PLN at all. In view of this, the present study was initiated to use all-atom molecular dynamics simulations to study the conformational dynamics of both bellflower and pinwheel models of PLN pentamer as well as their phosphorylated forms in POPC bilayer surroundings, so as to gain the atomistic insights into the internal motion of PLN pentamer and its functions. Similar approaches have been successfully used to investigate various problems related to protein structure, protein-protein interactions and protein-drug interactions, as well as drug design. Meanwhile, sodium ions were randomly placed to neutralize the simulated systems. Subsequently, Panaxadiol 150,000step energy minimization was performed on water molecules and ions for the monomeric systems using conjugate gradient and line search algorithm to remove energetically unfavorable contacts. Another 50,000 steps were added for the pentameric systems because of their larger sizes. In this procedure, both of the proteins and lipids were fixed. Then, all the systems were heated to 310 K over 500 ps by velocity rescaling, and equilibrated for 4 ns in the NPT ensemble with all non-hydrogen atoms of the protein and POPC membranes harmonically restrained. The equilibration was continued for another 10 ns with the harmonic restrain applied to the protein backbone only. Finally, the systems obtained at the end of the aforementioned equilibrations were used for the further unrestrained 40-ns MD simulations. As the simulated systems may be far too large to expect the statistical convergence in 40-ns MD simulations, we have done some repeats with different starting structures and starting vectors. Thus,Ginsenoside-Ro for each simulation, at least 10 MD trajectories with different starting vectors were generated. One possible explanation for this observation is that phosphorylation can increase the interactions of PLN with the lipid bilayer, resulting in the fact that the cytoplasmic domain no longer moves as freely as the unphosphorylated structure. Thus, after phosphorylation at Ser16, both models have to adopt a similar configuration, which is also supported by the previous theoretical studies. Accordingly, our theoretical studies supported the allosteric model to elucidate the interactions between PLN and SERCA, as illustrated in Fig. 4. According to the allosteric model, there is a dynamic equilibrium between the ‘‘extended’’ and ‘‘bent’’ conformations for PLN in the free form. The major difference between the extended and bent states for PLN is located on the cytoplasmic domain. For the extended state of PLN, the cytoplasmic domain is in a dynamically disordered state in which the central part of this domain is unfolded. For the bent state of PLN, this domain employs an ordered state. Both models can interact with SERCA, forming transition and active states respectively. However the phosphorylation at Ser16 reduces the structural difference between the PLN monomer in bellflower model and that in pinwheel model, revealing a structural transition between the ordered and disordered states in the cytoplasmic domain.