Functional Regulation of Aquaporin Dynamics by Lipid Bilayer Composition

Abstract

With the diversity of lipid-protein interactions, any observed membrane protein dynamics or functions directly depend on the lipid bilayer selection. However, the implications of lipid bilayer choice are seldom considered unless characteristic lipid-protein interactions have been previously reported. Using molecular dynamics simulation, we characterize the effects of membrane embedding on plant aquaporin SoPIP2;1, which has no reported high-affinity lipid interactions. The regulatory impacts of a realistic lipid bilayer, and nine different homogeneous bilayers, on varying SoPIP2;1 dynamics were examined. We demonstrate that SoPIP2;1s structure, thermodynamics, kinetics, and water transport are altered as a function of each membrane construct's ensemble properties. Notably, the realistic bilayer provides stabilization of non-functional SoPIP2;1 metastable states. Hydrophobic mismatch and lipid order parameter calculations further explain how lipid ensemble properties manipulate SoPIP2;1 behavior. Our results illustrate the importance of careful bilayer selection when studying membrane proteins. To this end, we advise cautionary measures when performing membrane protein molecular dynamics simulations.

Interplay between phosphorylation and oligomerization tunes the conformational ensemble of SWEET transporters

“…The number of processes plotted for implied timescale analysis was determined via spectral decomposition analysis (62, 63) ( Figure S2 ). The extent of stationary distribution reweighting was evaluated, with the goal of having the MSM-weighting deviate no more than 1.5 orders of magnitude above the raw distribution ( Figure S3 ) (64). Lastly, the Chapman-Kolmogorov test was performed to evaluate detailed balance at Markov lag times greater than the validated lag time but smaller than the total trajectory length ( Figure S4 ) (65–67).…”

“…Maximum complexity recipes (26) were used at sizes of 256 and 512 total lipids for monomer and trimer system construction, respectively. A distinct membrane packing was initialized for each of the input PDB states to help prevent unwanted lipid ensemble properties from impeding conformational sampling during simulations (26,40,41). The CHARMM default TIP3P water was used for solvation (42).…”

“…Subsequent NPT simulation was performed for 3 ns. Next, a 50 ns NPT equilibration run was performed as a "HOLD" step (26,40). Each of these above preparatory simulations were performed using protein backbone harmonic restraints at a strength of 5 kcal/mol/Å 2 .…”