Molecular dynamics (MD) simulations are widely implemented to study protein dynamics, but simulation results for membrane protein systems are largely confounded by the selected model lipid bilayer. While simulations with increasing membrane compositional complexity have been shown to enhance membrane protein conformational sampling, there exists a probability that some protein-lipid interactions may prove deleterious to resolving target protein conformations for a given ensemble. Thus the exact effects that each different lipid species within a complex mixture individually contributes to membrane protein dynamics must be investigated. Moreover, models for membrane protein simulations are often homogeneously constructed, which are not representative of real-world systems. Accordingly, the consequences of lipid selection on slower dynamical processes are yet to be examined systematically. Here, we quantify the effect of lipid bilayer simplification on long-timescale MD simulations. A plant aquaporin (AQP) is used as a model system in this study because of the general lack of specificity in AQP protein-lipid interactions, as well as plant AQPs demonstrating measurable conformational change mainly through pore plugging. To facilitate state exploration, classical MD with an adaptive sampling regime is performed on the SoPIP2;1 monomer system embedded in nine homogeneous, and one complex, lipid bilayers. Lipid-specific effects on AQP dynamics are statistically validated with Markov state models. A high sampling of intermediate states compared to the crystal structure states has been observed for several systems. Significant differences in mean-first-passage-time between metastable states are quantified. Analyses of water transport, lipid residence time, and membrane hydrophobic mismatch also portray the influence of each lipid species on AQP dynamics and function. Our study indicates that choice of lipid bilayer composition can drastically affect transition probabilities for membrane protein free energy landscapes.

Functional regulation of aquaporin dynamics by lipid bilayer composition

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