Impact of Increased Membrane Realism on Conformational Sampling of Proteins

Abstract

The realism and accuracy of lipid bilayer simulations through molecular dynamics (MD) are heavily dependent on the lipid composition. While the field is pushing toward implementing more heterogeneous and realistic membrane compositions, a lack of high-resolution lipidomic data prevents some membrane protein systems from being modeled with the highest level of realism. Given the additional diversity of real-world cellular membranes and protein–lipid interactions, it is still not fully understood how altering membrane complexity affects modeled membrane protein functions or if it matters over long-timescale simulations. This is especially true for organisms whose membrane environments have little to no computational study, such as the plant plasma membrane. Tackling these issues in tandem, a generalized, realistic, and asymmetric plant plasma membrane with more than 10 different lipid species is constructed herein. Classical MD simulations of pure membrane constructs were performed to evaluate how altering the compositional complexity of the membrane impacted the plant membrane properties. The apo form of a plant sugar transporter, OsSWEET2b, was inserted into membrane models where lipid diversity was calculated in either a size-dependent or size-independent manner. An adaptive sampling simulation regime validated by Markov-state models was performed to capture the gating dynamics of OsSWEET2b in each of these membrane constructs. In comparison to previous OsSWEET2b simulations performed in a pure POPC bilayer, we confirm that simulations performed within a native-like membrane composition alter the stabilization of apo OsSWEET2b conformational states by ∼1 kcal/mol. The free-energy barriers of intermediate conformational states decrease when realistic membrane complexity is simplified, albeit roughly within sampling error, suggesting that protein-specific responses to membranes differ due to altered packing caused by compositional fluctuations. This work serves as a case study where a more realistic bilayer composition makes unbiased conformational sampling easier to achieve than with simplified bilayers.

Comparative Molecular Dynamics Simulation Studies of Realistic Eukaryotic, Prokaryotic, and Archaeal Membranes

“…PMm contains the most abundant lipid types from the average human PM . PMp represents membranes of mung bean hypocotyl that have a more complex lipid mixture than previously modeled plant PMs containing up to 10 lipid types. , The lipid composition of PMf is similar to that of the previously modeled yeast PM, although half of sterol molecules is substituted by an inositol-containing SL, mannosyl-inositol-phosphoryl-ceramide (MIPC) based on the work of Hechtberger et al…”

“…Computational modeling and simulation of cell membranes give an opportunity to analyze protein behaviors in their natural membrane environment. It has been demonstrated that using realistic membrane complexity is essentia for reproducing the energetics of conformational transitions in membrane proteins …”

“…This required developments of tools for easy building of membranes with complex lipid compositions , and improvements to computational approaches . For example, all-atom MD simulations of membranes with nativelike lipid composition have been performed for the outer − and inner membranes of Gram-negative bacteria, − cell membrane of Gram-positive bacteria, archaebacterial membranes, PM and organelle membranes of yeast, − and PM of plants, , among others. These membrane systems usually included up to 600 lipids of 4–10 lipid types that were simulated on the nano- to microsecond (ns−μs) time scale.…”

Atomistic Insights Into The Mechanism of Dual Affinity Switching In Plant Nitrate Transporter NRT1.1

“…[23][24][25][26] MSMs have been recently used to investigate the conformational dynamics associated with membrane transporters. 19,24,[27][28][29][30][31] MSMs were constructed using MSMBuilder 3.6. 32 The simulation data was analyzed using MDTraj 33 .…”

Thirty years of molecular dynamics simulations on posttranslational modifications of proteins

“…The predictive power of MD simulations is limited insofar as the realism used to model the system. As efforts have been cast to make the modeling of lipid bilayers and membrane proteins match experiments with improved realism, 286 so too shall efforts surrounding PTM simulation strive to make our biophysical understanding of processes regulating protein function more complete.…”